Traumatic injury in the developing brain – effects of hypothermia

Little is known about the underlying mechanisms of head trauma in the developing brains, despite considerable social and economic impact following such injuries. Age has been shown to substantially influence morbidity and mortality. Children younger than 4 years of age had worse cognitive, motor, and brain atrophy outcomes than children 6 years of age and older. Younger children tend to more frequently suffer from diffuse cerebral swelling compared to adults. Typical autoptic findings also include axonal injury and ischemic neurodegeneration. These differences impact not only the primary response of the brain to injury but the secondary response as well. The complexity of damaging mechanisms in traumatic brain injury contributes to the problem of determining effective therapy. As an alternative/ adjunct to pharmacological approaches, hypothermia has been shown to be cerebroprotective in traumatized adult brains. Although a large number of animal studies have shown protective effects of hypothermia in a variety of damaging mechanisms after TBI, little data exist for young, developing brains. The injury mechanisms of TBI in the immature, effects of hypothermia following resuscitation on adult and immature traumatized brains, and some possible mechanisms of action of hypothermia in the immature traumatized brain are discussed in this review.     

Neuroprotective effects of resveratrol against traumatic brain injury in immature rats

Childhood trauma resulting in traumatic brain injury (TBI) due to accidents and abuse is the major cause of death and dysfunction in the young. Since there are no approved specific pharmacological agents that block the progression of the secondary injury, the current management of TBI is mainly supportive. We aimed to determine the effect of resveratrol on hippocampal damage and behavioral deficits in 7-day-old rat pups subjected to contusion injury. Resveratrol was injected intraperitoneally at the doses of 100 mg/kg of body weight immediately after induction of traumatic injury. Hippocampal damage was examined by cresyl violet staining and behavioral alterations were evaluated using open field and novel object recognition tests 2 weeks after trauma. Histopathological evaluation showed that treatment with a single dose of 100 mg/kg resveratrol (i.p.) after the trauma significantly ameliorated the trauma induced hippocampal neuron loss at ipsilateral and contralateral hippocampal brain regions of rats. Additionally, treatment with resveratrol decreased anxiety and increased cortex/hippocampus dependent memory of animals subjected to blunt head trauma. These results show that acute treatment of resveratrol has a neuroprotective role against trauma induced hippocampal neuron loss and associated cognitive impairment in rats.     

Evaluation of late cognitive impairment and anxiety states following traumatic brain injury in mice: The effect of minocycline

Comorbidity of cognitive and stress disorders is a common clinical sequel of traumatic brain injury (TBI) that is essentially determined by the site and severity of the insult, but also by the extent of the ensuing neuroinflammatory response. The present study sought to examine the late effects of closed-head TBI on memory function and anxiety in mice, in order to further examine the potential efficacy of an acute anti-inflammatory treatment with minocycline. The mouse model of closed-head injury by mechanical percussion was applied on anesthetized Swiss mice. The treatment protocol included three injections of minocycline (i.p.) at 5 min (90 mg/kg), 3 h and 9 h (45 mg/kg) post-TBI. The Novel Object Recognition Test as well as the Elevated Plus Maze (EPM) and Elevated Zero Maze (EZM) tasks were employed to assess post-TBI memory and anxiety respectively. Our results revealed a recognition memory deficit that was significant up to at least 13 weeks post-TBI. However, neither EPM nor EZM revealed any alteration in post-TBI anxiety levels albeit some mild disinhibition. Most importantly, minocycline was able to attenuate the memory impairment in an effective and lasting manner, highlighting its therapeutic potential in TBI.     

脑微损伤的影像学进展

脑微损伤是创伤性脑损伤最常见的类型,然而,其潜在的神经生理机制尚未完全阐明,影响患者的早期诊断、治疗及预后评估。近年来,多项磁共振（MRI）新技术不断地涌现并用于评估脑微损伤,如功能磁共振、灌注MRI、弥散张量成像、定量易感性图谱、T2 mapping等。本研究综述了多模态MRI在脑微损伤中的应用,从不同的角度深入地了解脑微损伤的神经病理机制,有助于提高临床医生对脑微损伤的诊断和治疗。     

Oligodendrocyte vulnerability following traumatic brain injury in rats

Experimental and clinical findings demonstrate that traumatic brain injury (TBI) results in injury to both gray and white matter structures. The purpose of this study was to document patterns of oligodendrocyte vulnerability to TBI. Sprague Dawley rats underwent sham operated procedures or moderate fluid percussion brain injury. Quantitative immunohistochemical analysis was performed on animals perfusion-fixed at 3 (n=9) or 7 (n=9) days post-surgery. Within the ipsilateral external capsule and corpus callosum, numbers of APC-CC1 immunoreactive oligodendrocytes were significantly decreased at 3 or 7 days post-TBI compared to sham rats (p<0.03). At both posttraumatic survival periods, double-labeling studies indicated that oligodendrocytes showed increased Caspase 3 activation compared to sham. These data demonstrate regional patterns of oligodendrocyte vulnerability after TBI and that oligodendrocyte cell loss may be due to Caspase 3-mediated cell death mechanisms. Further studies are needed to test therapeutic interventions that prevent trauma-induced oligodendrocyte cell death, subsequent demyelination and circuit dysfunction.     

Drug-induced apoptotic neurodegeneration in the developing brain

Physiological cell death (PCD), a process by which redundant or unsuccessful neurons are deleted by apoptosis (cell suicide) from the developing central nervous system, has been recognized as a natural phenomenon for many years. Whether environmental factors can interact with PCD mechanisms to increase the number of neurons undergoing PCD, thereby converting this natural phenomenon into a pathological process, is an interesting question for which new answers are just now becoming available. In a series of recent studies we have shown that 2 major classes of drugs (those that block NMDA glutamate receptors and those that promote GABAA receptor activation), when administered to immature rodents during the period of synaptogenesis, trigger widespread apoptotic neurodegeneration throughout the developing brain. In addition, we have found that ethanol, which has both NMDA antagonist and GABAmimetic properties, triggers a robust pattern of apoptotic neurodegeneration, thereby deleting large numbers of neurons from many different regions of the developing brain. These findings provide a more likely explanation than has heretofore been available for the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome (FAS). The period of synaptogenesis, also known as the brain growth spurt period, occurs in different species at different times relative to birth. In rats and mice it is a postnatal event, but in humans it extends from the sixth month of gestation to several years after birth. Thus, there is a period in pre- and postnatal human development, lasting for several years, during which immature CNS neurons are prone to commit suicide if exposed to intoxicating concentrations of drugs with NMDA antagonist or GABAmimetic properties. These findings are important, not only because of their relevance to the FAS, but because there are many agents in the human environment, other than ethanol, that have NMDA antagonist or GABAmimetic properties. Such agents include drugs that may be abused by pregnant mothers (ethanol, phencyclidine [angel dust], ketamine [Special K], nitrous oxide [laughing gas], barbiturates, benzodiazepines), and many medicinals used in obstetric and pediatric neurology (anticonvulsants), and anesthesiology (all general anesthetics are either NMDA antagonists or GABAmimetics).     

Effect of APOE polymorphisms on early responses to traumatic brain injury

To investigate the relationship between apolipoprotein E (APOE) polymorphisms and the severity of traumatic brain injury (TBI) in acute stage in the cohort of mainland Chinese patients. We prospectively identified admissions to the two neurosurgical departments for head injury. A total of 110 subjects with TBI (80 males and 30 females, with mean age of 43.87 years) were enrolled from December 2003 to May 2004, and demographic and clinical data were collected. Venous blood was collected from patients with TBI on admission to determine the APOE genotype polymorphisms. The APOE genotyping was performed by means of PCR-RFLP. The deterioration of patients’ condition in acute stage (<7 days after TBI) was judged by either of following criteria: decrease of GCS, increase in hematoma volume or delayed hematoma both detected by repeated CT scanning. χ²-test and logistic regression analyses were done by SPSS. The distributions of APOE genotypes and alleles matched Hardy–Weinberg law. In 110 Chinese patients, 19 subjects presented with deteriorated clinical condition after hospitalization, and seven of 17 patients with APOE ?4 (41.2%) had a deteriorated condition which was significantly different from those without APOE ?4 (12 of 93 patients, 12.9%, P = 0.01). However, neither the presence of ?2 nor of ?3 was significantly different from those absent of it (P > 0.05). Logistic regression analyses showed that APOE ?4 was a risk factor (OR = 4.836, P = 0.011, 95% CI 1.443–16.208) to predispose to clinical deterioration after adjusting for patient age, sex, smoking or not, alcohol-drinking or not, injury severity, injury mechanisms, treatments, and pattern of TBI. This finding suggests that the patients with APOE ?4 predispose to clinical deterioration in acute phase after TBI and APOE polymorphisms play a role in early responses to TBI.     

血必净在心肺复苏大鼠脑损伤中的神经保护作用

目的探讨中成药血必净对心肺复苏模型大鼠脑损伤的神经保护作用及相关机制。方法采用Utstein模式建立心肺复苏大鼠模型,45只SD大鼠随机分成假手术组、血必净组和生理盐水组。血必净组和生理盐水组在建立心肺复苏大鼠模型后分别给予腹腔注射血必净和生理盐水。10d后采集鼠脑连冷冻切片后利用3DDoctor三维重建血必净组和生理盐水组大鼠脑损伤区域并测算脑损伤面积与体积;TUNEL法检测各组大鼠脑损伤区域神经细胞凋亡情况。结果成功建立心肺复苏大鼠模型,模型制作成功率50%;三维重建生理盐水组和血必净组大鼠鼠脑,经3D-Doctor 4.0测算,血必净组鼠脑皮质损伤面积和梗死灶体积均低于生理盐水组,P0.05;心肺复苏模型大鼠脑损伤区周围皮质出现凋亡细胞;给予血必净治疗后,与生理盐水组比较,血必净可以下调损伤区周围皮质神经细胞的凋亡指数(AI)。结论大鼠心肺复苏脑损伤后,给予血必净治疗后能减少大鼠脑内皮质损伤区面积和梗死灶体积,抑制损伤区周围皮质神经细胞的凋亡,具有神经保护作用。     

Sensitivity of the comprehensive trail making test to traumatic brain injury in adolescents

The current study examined the sensitivity of the Comprehensive Trail Making Test (CTMT Reynolds) to neurocognitive deficits in adolescents with traumatic brain injury (TBI). Participants included 60 adolescents, 30 who had sustained TBI and 30 healthy controls (HC) that were individually matched to the TBI sample on age, gender, ethnicity, and geographical region. For both the TBI and HC groups the mean age was 15.0 years (S.D. = 2.3 years, range = 11–19). The TBI group had a mean IQ of 81.7 (S.D. = 14.9), had sustained moderate to severe brain injury, and was assessed an average of 21.1 months (S.D. = 20.7) following injury. The TBI group performed approximately 2 standard deviations below the control sample mean on each of the five CTMT trails as well as on the composite index and these differences were significant (p < .001). Significant correlations were present between the CTMT trails and clinical variables associated with brain injury severity. Finally, receiver operating characteristic analyses indicated good classification of the TBI and control cases for the CTMT, although some variability in classification accuracy was present among the various trails. Results suggest that the CTMT is sensitive to TBI in adolescents but continued research is needed with larger samples of individuals with TBI and other types of neurological disorders to further establish the present findings.     

Sleep disturbances following mild traumatic brain injury in childhood

OBJECTIVE: To examine objective and subjective reports of sleep disturbance in school-aged children who had sustained mild traumatic brain injury (TBI) at least 6 months prior to the study. METHODS: Eighteen children aged 7-12 years with a history of mild TBI (GCS 13-15. LOC < 15 min) were compared to 30 children with orthopedic injuries using actigraphy and parental and self-report sleep questionnaires. RESULTS: Parents reported greater sleep disturbance in the mild TBI group. No significant differences were found in parental ratings of daytime sleepiness, child-reported sleep difficulties, or objective (actigraph) sleep measures. CONCLUSIONS: The finding of greater parental reports of sleep disturbance following mild TBI 6 months after injury requires greater exploration and future research with a larger sample followed from the point of injury would seem appropriate.     

AMPA-induced dark cell degeneration is associated with activation of caspases in pyramidal neurons of the rat hippocampus

Various neurons in the central nervous system (CNS) exhibit selective vulnerability to AMPA-induced delayed neurotoxicity known as dark cell degeneration. Hippocampal pyramidal neurons in the CA1 and CA3 regions display such vulnerability that encompasses morphological changes including cytoplasmic and nuclear condensation, neuronal shrinkage, formation of cytoplasmic vacuoles, and general failure of physiology. The present study was undertaken to ascertain the potential involvement of initiator (caspase-9) and executor (caspase-3) caspases in AMPA-receptor-induced dark cell degeneration in pyramidal neurons. Immunohistochemical analyses revealed that immunoreactivity of the active form of caspase-9 and -3 was increased in pyramidal neurons in CA1 and CA3 regions of the hippocampus following AMPA (100 microM). Elevated levels of active caspase-9 immunoreactivity generally preceded elevations in active caspase-3 immunoreactivity. The pan caspase inhibitor FK011 effectively attenuated AMPA-induced dark cell degeneration in both CA1 and CA3 regions. Collectively, the data suggest a role for these caspases in mediating AMPA-induced toxicity in pyramidal neurons of the rat hippocampus.     

Delayed sodium pyruvate treatment improves working memory following experimental traumatic brain injury

Protein kinase C (PKC) is a family of serine/threonine-isozymes that are involved in many signaling events in normal and disease states. Previous studies from our lab have demonstrated that ?PKC plays a pivotal role in neuroprotection induced by ischemic preconditioning. However, the role of ?PKC during and after brain ischemia is not clearly defined. Therefore, in the present study, we tested the hypothesis that activation of ?PKC during an ischemic event is neuroprotective. Furthermore, other studies have demonstrated that ?PKC mediates cerebral ischemic tolerance in the rat brain by decreasing vascular tone. Thus, we also tested the effects of ?PKC activation during ischemia on cerebral blood flow (CBF). We found that ψ?-Receptors for Activated C Kinase (RACK), a ?PKC-selective peptide activator, injected intravenously 30 min before induction of global cerebral ischemia conferred neuroprotection in the CA1 region of the rat hippocampus. Moreover, measurements of CBF before, during, and after cerebral ischemia revealed a significant reduction in the reperfusion phase of rats pretreated with ψ?RACK as compared to Tat peptide (vehicle). Our results suggest that ?PKC can protect the rat brain against ischemic damage by regulating CBF. Thus, ?PKC may be one of the treatment modalities against ischemic injury.     

Apolipoprotein E genotype and oxidative stress response to traumatic brain injury

Traumatic Brain Injury (TBI) is known to result in oxidative stress, and as variation at the Apolipoprotein E (APOE) gene has been shown to influence outcome following TBI, but through as yet unclear mechanisms, we used transgenic APOE mouse models to examine the relationship between APOE genotype and oxidative stress following TBI. We administered a controlled cortical impact (CCI) injury or sham injury to transgenic mice expressing either human APOE3 or APOE4 on a murine APOE-deficient background. RNA was prepared from the ipsilateral hippocampi and cortices retrieved at 24 h and 1 month post-TBI. Microarray analysis was performed on unpooled samples from three mice per group to determine the genomic response to TBI and to specifically investigate the response of genes involved in oxidative stress mechanisms. Our data demonstrated TBI-induced expression of many more anti-oxidant related genes in the APOE3 mice, suggesting a potential anti-oxidative role for ApoE3 compared to ApoE4. However, in an additional cohort of mice we isolated the ipsilateral hippocampi, cortices, and cerebella at 1 month after TBI or sham injury for immunohistochemical analysis of markers of oxidative stress: the formation and presence of carbonyls (indication of general oxidative modification), 3-nitrotyrosine (3NT; specific to protein modification), or 4-hydroxyl-2-nonenal (HNE; specific to lipid peroxidation). Although we observed significant increases in all three markers of oxidative stress in response to injury, and genotype was a significant factor for carbonyl and 3NT, we found no significant interaction between genotype and injury. This may be due to the overwhelming effect of injury compared to genotype in our ANOVA, but nonetheless suggests that an influence on oxidative stress response is not the primary mechanism behind the APOE-genotype dependent effects on outcome following TBI.     

大鼠创伤性脑损伤后星形胶质细胞的变化

目的：探讨大鼠创伤性脑损伤后星形胶质细胞的形态学变化及GFAP和NOS的表达情况。方法：采用大鼠自由落体脑损伤模型，伤后1、3、7d取脑切片，行Nissl染色以及GFAP免疫组化和NADPH—d组化单标记及双标记染色。结果：损伤区周围皮质GFAP阳性细胞胞体增大、突起增粗增长，GFAP阳性细胞数量与正常侧及对照组相比，伤后1d即有明显增加，伤后3d、7d数量持续增加；损伤侧海马CAI～3区和DG各层GFAP阳性细胞排列紊乱，胞体增大、突起增粗增长，GFAP阳性细胞数量与正常侧及对照组相比则无明显变化。损伤区周围皮质、损伤侧海马NOS阳性细胞数量明显增加。伤后3d损伤区周围皮质和损伤侧海马中GFAP与NOS双标细胞分别占GFAP阳性细胞的14．2％和13．4％左右。结论：大鼠创伤性脑损伤后大量的星形胶质细胞活化、GFAP表达增加并且部分转化为NOS阳性细胞，提示其参与了脑组织的损伤与修复过程。     

Impaired emotional contagion following severe traumatic brain injury

Empathy deficits are widely-documented in individuals after severe traumatic brain injury (TBI). This study examined the relationship between empathy deficits and psychophysiological responsivity in adults with TBI to determine if impaired responsivity is ameliorated through repeated emotional stimulus presentations. Nineteen TBI participants (13 males; 41 years) and 25 control participants (14 males; 31 years) viewed five repetitions of six 2-min film clip segments containing pleasant, unpleasant, and neutral content. Facial muscle responses (zygomaticus and corrugator), tonic heart rate (HR) and skin conductance level (SCL) were recorded. Mean responses for each viewing period were compared to a pre-experiment 2-min resting baseline period. Self-reported emotional empathy was also assessed. TBI participants demonstrated identical EMG response patterns to controls, i.e. an initial large facial response to both pleasant and unpleasant films, followed by habituation over repetitions for pleasant films, and sustained response to unpleasant films. Additionally, an increase in both arousal and HR deceleration to stimulus repetitions was found, which was larger for TBI participants. Compared to controls, TBI participants self-reported lower emotional empathy, and had lower resting arousal, and these measures were positively correlated. Results are consistent with TBI producing impairments in emotional empathy and responsivity. While some normalisation of physiological arousal appeared with repeated stimulus presentations, this came at the cost of greater attentional effort.     

颅脑外伤后并发低钠血症的危险因素分析

目的探讨颅脑外伤患者并发低钠血症的发生机制及危险因素,以期为其早期预测及预防提供参考。方法回顾性分析2016年6月至2019年6月我院收治的185例中型和重型颅脑外伤患者的临床资料,包括导致低钠血症的不同病因、损伤类型、性别、格拉斯哥昏迷(GCS)评分、手术、脑水肿、颅底骨折和穿透性性损伤等;采用单因素χ^2检验和多因素Logistic回归分析探究颅脑外伤后并发低钠血症的危险因素。结果所有患者中,80例出现低钠血症,其中钠盐摄入不足、利尿剂过量使用47例,抗利尿激素分泌失调综合征19例,脑性耗盐综合征14例。低钠血症更多发生在脑挫裂伤、蛛网膜下腔出血和弥漫性轴索损伤患者中,差异具有统计学意义(P<0.05)。单因素χ^2检验结果显示,GCS评分(P=0.000)、脑水肿(P=0.000)、颅底骨折(P=0.000)、穿透性损伤(P=0.001)是颅脑外伤后并发低钠血症的相关因素。多因素Logistic回归分析结果显示,GCS评分(P=0.006)、脑水肿(P=0.006)、颅底骨折(P=0.000)、穿透性损伤(P=0.015)是颅脑外伤后并发低钠血症的危险因素。结论脑挫裂伤、蛛网膜下腔出血、弥漫性轴索损伤、GCS评分≤8分、脑水肿、颅底骨折和穿透性损伤的颅脑外伤患者更易发生低钠血症,应早期关注患者血清钠水平,明确病因及时纠正,防止病情恶化。     

Apolipoprotein E-genotype dependent hippocampal and cortical responses to traumatic brain injury

The different alleles of the apolipoprotein E gene (APOE-gene, ApoE-protein) have been reported to influence recovery after traumatic brain injury (TBI) in both human patients and animal models, with the e4 allele typically conferring poorer prognosis for recovery. How the E4 allele, and consequently the ApoE4 isoform, affects recovery is unknown, but proposed mechanisms include neurogenesis, inflammatory response and amyloid processing or metabolism. Using the controlled cortical impact (CCI) model of brain injury and microarray technology we have characterized the genomic response to injury in the brains of APOE2, APOE3 and APOE4 transgenic mice and identified quantitatively and qualitatively significantly different profiles of gene expression in both the hippocampus and the cortex of the APOE3 mice compared to APOE4. The observed gene regulation predicts functional consequences including effects on inflammatory processes, cell growth and proliferation, and cellular signaling, and may suggest that the poor recovery post-TBI in APOE4 animals and human patients is less likely to result from a specific activation of neurodegenerative mechanisms than a loss of reparative capability.     

Sex differences in XIAP cleavage after traumatic brain injury in the rat

Sex influences histological and behavioral outcomes following traumatic brain injury (TBI), but the underlying sex-dependent pathomechanisms regulating outcome measures remain poorly defined. Here, we investigated the TBI-induced regulation of the X-linked inhibitor of apoptosis protein (XIAP) that, in addition to suppressing cell death by inhibition of caspases, is involved in signaling cascades, including immune regulation and cell migration. Since estrogen has been shown to have anti-apoptotic properties, we specifically examined sex differences and the influence of estrogen on XIAP processing after TBI. Sprague–Dawley male (TBI-M), female (TBI-F), ovariectomized female (TBI-OVX) and ovariectomized females supplemented with estrogen (TBI-OVX + EST) were subjected to moderate (1.7–2.2 atm) fluid percussion (FP) injury. Animals were sacrificed 24 h after FP injury; cortical tissue (ipsilateral and contralateral) was dissected and analyzed for XIAP processing by immunoblot analysis (n = 6–7/group) or confocal microscopy (n = 2–3/group). Significant differences in XIAP cleavage products in the ipsilateral cortex were found between groups (p < 0.03). Post hoc analysis showed an increase in XIAP processing in both TBI-F and TBI-OVX + EST compared to TBI-M and TBI-OVX (p < 0.05), indicating that more XIAP is cleaved following injury in intact females and TBI-OVX + EST than in TBI-M and TBI-OVX groups. Co-localization of XIAP within neurons also demonstrated sex-dependent changes. Based on these data, it appears that the processing of XIAP after injury is different between males and females and may be influenced by exogenous estrogen treatment.     

Memory and executive functions correlates of self-awareness in traumatic brain injury

Objective: The purpose of this study was to investigate the contribution of executive functions (EF) components and episodic and working memory variables, as well as clinical and demographic factors, to awareness of cognitive ability in traumatic brain injury (TBI).

Methods: Sixty-five TBI patients (mild: n?=?26; moderate/severe: n?=?39) took part in the study. Independent stepwise regression models were calculated for EF and memory predictors, with awareness being measured by patient/informant discrepancy in the Patient Competency Rating Scale.

Results: Models with EF variables indicated that semantic verbal fluency and age are the best predictors of awareness, whereas models including mnemonic functions suggested verbal delayed episodic recall and TBI severity as predictors.

Conclusions: These results are discussed in relation to clinical implications, such as the need to focus efforts of rehabilitation in the cognitive abilities related to awareness, and theoretical models.     

脑外伤小鼠海马血管内皮生长因子表达的变化

目的探讨脑外伤小鼠海马血管内皮生长因子(vascular endothelial growth factor,VEGF)表达的变化。方法 40只Balb/c小鼠随机分为2组,假手术组(10只)和脑外伤组(30只)。脑外伤组依据脑外伤的不同时间点再分6h、1d、3d三个小组,每组10只。免疫组化和Western blot检测各组小鼠海马VEGF蛋白的表达。RT-PCR方法检测各组小鼠海马VEGF mRNA的表达变化。结果免疫组化和Western blot结果发现,脑外伤组小鼠海马VEGF蛋白表达量明显高于假手术组(<0.05);RT-PCR结果也发现,脑外伤组小鼠海马VEGF mRNA表达量明显高于假手术组(<0.05)。结论脑外伤小鼠海马VEGF表达明显升高。