Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies

Most current treatments for epilepsy are symptomatic therapies that suppress seizures but do not affect the underlying course or prognosis of epilepsy. The need for disease-modifying or "antiepileptogenic" treatments for epilepsy is widely recognized, but no such preventive therapies have yet been established for clinical use. A rational strategy for preventing epilepsy is to target primary signaling pathways that initially trigger the numerous downstream mechanisms mediating epileptogenesis. The mammalian target of rapamycin (mTOR) pathway represents a logical candidate, because mTOR regulates multiple cellular functions that may contribute to epileptogenesis, including protein synthesis, cell growth and proliferation, and synaptic plasticity. The importance of the mTOR pathway in epileptogenesis is best illustrated by tuberous sclerosis complex (TSC), one of the most common genetic causes of epilepsy. In mouse models of TSC, mTOR inhibitors prevent the development of epilepsy and underlying brain abnormalities associated with epileptogenesis. Accumulating evidence suggests that mTOR also participates in epileptogenesis due to a variety of other causes, including focal cortical dysplasia and acquired brain injuries, such as in animal models following status epilepticus or traumatic brain injury. Therefore, mTOR inhibition may represent a potential antiepileptogenic therapy for diverse types of epilepsy, including both genetic and acquired epilepsies.     

Prospective memory in patients with closed head injury: a review

This paper aimed to review the limited, but growing literature on prospective memory (PM) following closed head injury (CHI). Search of two commonly used databases yielded studies that could be classified as: self- or other-report of PM deficits; behavioral PM measures in adults with CHI, behavioral PM measures in children and adolescents with CHI, and treatment of PM in adults with CHI. The methodology and findings of these studies were critically reviewed and discussed. Because of the small number of studies, meta-analysis was only conducted for studies that used behavioral PM measures in adults to integrate findings. PM deficits were found to be commonly reported by patients with CHI and their significant others and they could be identified using behavioral measures in adults, children and adolescents with CHI. However, more work is needed to clarify the nature and mechanisms of these deficits. Although some promising results have been reported by studies that evaluated PM treatment, most studies lack tight experimental control and used only a small number of participants. The paper concluded with some suggestions for future research.     

The genomic profile of the cerebral cortex after closed head injury in mice: effects of minocycline

Microarray analysis was used to delineate gene expression patterns and profile changes following traumatic brain injury (TBI) in mice. A parallel microarray analysis was carried out in mice with TBI that were subsequently treated with minocycline, a drug proposed as a neuroprotectant in other neurological disorders. The aim of this comparison was to identify pathways that may be involved in secondary injury processes following TBI and potential specific pathways that could be targeted with second generation therapeutics for the treatment of neurotrauma patients. Gene expression profiles were measured with the compugen long oligo chip and real-time PCR was used to validate microarray findings. A pilot study of effect of minocycline on gene expression following TBI was also carried out. Gene ontology comparison analysis of sham TBI and minocycline treated brains revealed biological pathways with more genes differentially expressed than predicted by chance. Among 495 gene ontology categories, the significantly different gene ontology groups included chemokines, genes involved in cell surface receptor-linked signal transduction and pro-inflammatory cytokines. Expression levels of some key genes were validated by real-time quantitative PCR. This study confirms that multiple regulatory pathways are affected following brain injury and demonstrates for the first time that specific genes and molecular networks are affected by minocycline following brain injury. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

颅脑创伤后大鼠海马CA1锥体细胞内在电生理和兴奋性突触传递特性的变化

目的 在细胞及突触水平探讨外伤后癫痫的发病机制.方法 自由落体致伤法制备大鼠颅脑创伤模型,采用膜片钳技术监测海马CA1区锥体细胞内在电生理特性和局部突触兴奋性的变化.结果 颅脑创伤后,大鼠CA1锥体细胞膜输入阻抗和时间常数增加,动作电位的阈电流降低;给予配对刺激后,海马CA1区兴奋性突触后电流表现为配对脉冲比率的降低及配对脉冲易化向配对脉冲抑制的转变.结论 颅脑创伤后海马CA1区神经元内在兴奋性和突触传递功能增强,这些改变可能是外伤后癫痫发病的重要原因.     

脑外伤患者恢复期的注意障碍

目的探索脑外伤恢复期患者注意的改变及其特征.方法对42例大型医院神经外科住院治疗的脑外伤恢复期患者和42名正常人进行"2,7"划消测验和Strop测验.结果脑外伤患者在标准情况、不相关分心情况和相关分心情况下的划消速度明显低于正常对照组,而精确率无明显差异.进一步比较相关分心情况下划消速度的下降率显示脑外伤患者显著大于正常对照组.Stroop测验显示脑外伤患者读单色字时间、读色块时间和读彩色字颜色时间较正常对照组显著延长,但两组之间错误数无显著性差异.比较两组读彩色字颜色时间的延长率和读彩色字文字时间的延长率,脑外伤患者均显著大于对照组.结论脑外伤后患者的注意力下降.注意的分配受损,抗干扰能力下降,而选择注意相对完整.     

Heightened false memory: a long-term sequela of severe closed head injury

Declarative memory impairment is a common long-term sequela of severe closed head injury (CHI). Although veridical memory performance following severe CHI has received attention in the literature, little is known about false memory production in this population. Within the present study, both long-term survivors of severe CHI and matched control participants studied and were tested on six 12-items word lists from the Deese Roediger McDermott (DRM) paradigm. Word lists from the DRM are composed of words that are strongly semantically associated to a non-presented word (i.e., the critical lure). Prior studies have shown that healthy young adults show a high level of false recall and recognition memory for the critical lures, and it was hypothesized individuals with severe CHI would show heightened susceptibility to false memory compared to control participants due to difficulty with monitoring of memory. It was further hypothesized that severe CHI participants would show high confidence in their false memories. Consistent with hypotheses, results indicated that although severe CHI participants remembered fewer actual list items, they made more semantically related intrusion errors (recall) and false-positive responses (recognition) than the control participants. Severe CHI participants also showed greater confidence in their false memories than did control participants. The results are interpreted in the context of theoretical accounts of false memory, and possible structural and functional brain changes that might account for the Severe CHI group's memory performance are discussed.     

Management and classification of children with head injury

Background Traumatic brain injury is the most common cause of morbidity and mortality during childhood.Aim This study was conducted to describe the primary management and classification of children admitted to the emergency department for head trauma.Series All children (0–15 years) with a history of head injury who were admitted to the outpatient emergency department at a single paediatric trauma centre in the Stockholm region during 1 month were included.Results There were 242 children (137 girls and 105 boys; mean age 5.3±4.4 years) who fulfilled the inclusion criteria. Based on the Scandinavian Head Injury Classification, 73% were classified as minimal, 17% mild and 2% moderate head injury. This classification seemed to be more accurately reflective than the ICD-10-based classification in the management of the children with head trauma.     

Neuronal injury and loss after traumatic brain injury: time course and regional variability

We have examined regional neuronal injury after traumatic brain injury using Fluoro-Jade, an acidic dye that exhibits a marked affinity for both the degenerating neuronal cell body and its processes and have determined the extent to which early injury corresponds to regional patterns of neuronal loss. Rats (n=45) were subjected to lateral fluid percussion brain injury and euthanized at 3 h to 28 days post injury. Complementary Fluoro-Jade, silver impregnation methods and TUNEL were used to assess neuronal injury. Neuronal loss was evaluated in sections immunostained for NeuN, a neuronal specific nuclear protein. Overt neuronal cell loss was evident by 7 days post injury in the cortex, hippocampus and thalamus. Injured neurons were apparent in the ipsilateral cortex bordering the impact site, hippocampus (CA1 and dentate), thalamus, and vermis of the cerebellum as early as 3 h post injury. Degenerating neurons were maximal by 1 and 3 days in the cortex and hippocampus, by 3 and 7 days in the cerebellum, and by 7 days in the thalamus. The regional distribution of Fluoro-Jade-labeled neurons corresponded to a similar pattern of silver and TUNEL staining. Together, these findings demonstrate a regionally specific temporal pattern of neuronal injury that results in overt neuronal cell loss within both cortical and subcortical regions.     

颅脑外伤对患者智能状况的影响及相关因素研究

目的：研究颅脑外伤对患者智能状况的影响,探讨与之相关的生物、心理、社会因素。方法：本研究对63例急性期颅脑外伤患者,采用标准化测评工具,包括《格拉斯哥昏迷评分（GCS）》、《简易智力状态检查》、《数字划消测验》、《社会支持评定量表》、《日常生活能力量表》及自制颅脑外伤患者人口学与相关因素调查表等,逐例进行现场临床测评,将拟分析的因素进行量化,最后将汇总的资料进行整理,分析、总结。所有统计分析均使用SAS软件包完成。结果：颅脑外伤患者智能缺陷的发生率为71．43％,其显著性差异表现在文化程度、治疗措施及手术类型三个方面,主要影响因素有外伤程度、外伤部位、社会支持、文化程度及治疗措施。结论：不同外伤类型的颅脑外伤对患者的智能状 况产生不同程度的影响,其相关因素包括生物、心理、社会学三个方面,基础的生物学病因虽然对智能起决定作用,而社会心理因素的影响仍不可忽视。     

重型颅脑损伤后并发精神障碍临床分析

目的回顾分析重症颅脑损伤后并发精神障碍。方法总结我院1998-10~2006-10收治的重症颅脑损伤后并发精神障碍46例病人,分析伤情、受伤部位与并发的精神障碍间的关系。结果本组病人共出现4型精神障碍:躁狂型、抑郁型、精神分裂样型、痴呆型。损伤部位分别为:额叶损伤、颞叶损伤、胼胝体损伤、脑干损伤。损伤类型为:脑挫伤、弥漫性轴索损伤(DAI)、脑挫伤并发颅内血肿或并发脑疝。结论额叶脑挫伤或颞叶脑挫伤并发躁狂型精神障碍最多见,脑干损伤及DAI常出现痴呆型精神障碍。     

Epilepsy in the Developing Brain: Lessons from the Laboratory and Clinic

Summary: Children with epilepsy present unique challenges to the clinician. In addition to having differences in clinical and EEG phenomena, children differ from adults in regard to etiological factors, response to antiepileptic drugs (AEDs), and outcome. It is now recognized that the immature brain also differs from the mature brain in the basic mechanisms of epileptogenesis and propagation of seizures. The immature brain is more prone to seizures due to an imbalance between excitation and inhibition. γ-Aminobutyric acid (GABA), the major CNS inhibitory neurotransmitter in the mature brain, can lead to depolarization in the hippocampal CA3 region in very young rats. There are also age-related differences in response to GABA agonists and antagonists in the substantia nigra, a structure important in the propagation of seizures. These age-related differences in response to GABAergic agents provide further evidence that the pathophysiology of seizures in the immature brain differs from that in the mature brain. Although prolonged seizures can cause brain damage at any age, the extent of brain damage after prolonged seizures is highly age dependent. Far less histological damage and fewer disturbances in cognition result from prolonged seizures in the immature brain than from seizures of similar duration and intensity in mature animals. However, detrimental effects of AEDs may be greater in the immature brain, than in the mature brain. These lessons from the animal laboratory raise questions about the appropriateness of current therapeutic approaches to childhood seizure disorders.     

Posttraumatic epilepsy after controlled cortical impact injury in mice

Many patients develop temporal lobe epilepsy after trauma, but basic mechanisms underlying the development of chronic seizures after head injury remain poorly understood. Using the controlled cortical impact injury model we examined whether mice developed spontaneous seizures after mild (0.5 mm injury depth) or severe (1.0 mm injury depth) brain injury and how subsequent posttraumatic mossy fiber sprouting was associated with excitability in the dentate gyrus 42–71 d after injury. After several weeks, spontaneous behavioral seizures were observed in 20% of mice with mild and 36% of mice with severe injury. Mossy fiber sprouting was typically present in septal slices of the dentate gyrus ipsilateral to the injury, but not in control mice. In slices with mossy fiber sprouting, perforant path stimulation revealed a significant reduction (P < 0.01) in paired-pulse ratios in dentate granule cells at 20 ms and 40 ms interpulse intervals, but not at 80 ms or 160 ms intervals. These slices were also characterized by spontaneous and hilar-evoked epileptiform activity in the dentate gyrus in the presence of Mg²⁺-free ACSF containing 100 μM picrotoxin. In contrast, paired-pulse and hilar-evoked responses in slices from injured animals that did not display mossy fiber sprouting were not different from controls. These data suggest the development of spontaneous posttraumatic seizures as well as structural and functional network changes associated with temporal lobe epilepsy in the mouse dentate gyrus by 71 d after CCI injury. Identifying experimental injury models that exhibit similar pathology to injury-induced epilepsy in humans should help to elucidate the mechanisms by which the injured brain becomes epileptic.     

脑外伤后进展性出血性脑损伤的诊治体会

目的研究脑外伤后进展性出血性脑损伤的临床特点,总结其发病机制,探讨及时诊断、治疗的方法。 方法回顾性分析解放军第二五一医院神经外科自2015年1月至2017年6月收治的167例脑外伤后进展性出血性脑损伤患者的临床资料。本组患者入院时按GCS评分：3~5分11例,6~8分36例,9~12分83例,13~15分37例。临床表现均有不同程度的颅高压症状,观察治疗过程中,76例患者出现意识障碍或意识障碍加深,94例患者肢体肌力减退,81例患者频繁呕吐,43例患者躁动,5例患者脑疝。 结果手术治疗94例,保守治疗73例。所有患者依据GOS评分判断：恢复良好114例,中残32例,重残13例,死亡8例（4.8%）。 结论动态CT观察是早期发现进展性出血性脑损伤的有效方法。对外伤性颅内血肿的患者绝不能仅仅依赖首次CT结果即制定一成不变的治疗方案,应进行专科监测和动态CT观察,根据患者血肿量的变化及时调整治疗方案。     

Neural correlates of self-evaluative accuracy after traumatic brain injury

Individuals who have sustained a traumatic brain injury (TBI) often exhibit an array of cognitive deficits, yet perhaps most maladaptive of these sequelae is the frequent occurrence of reduced insight into one's own condition. In such cases, TBI individuals may overestimate their post-injury level of socio-cognitive functioning, leading to disparities between how they perceive themselves and what others observe. This functional MRI (fMRI) investigation examined the relationship between level of insight into one's post-injury condition (i.e. trait/ability status) and neural activation evoked during an fMRI task involving self-appraisal of one's traits and abilities. Twenty TBI patients (8-12 weeks post-injury, ER Glasgow Coma Scale Average = 10.9+/-2.8) were selected on the criterion that they overestimate their current trait/abilities (as detected on the patient competency rating scale, PCRS). fMRI activation on the self-appraisal task was compared between the TBI patients and 20 matched controls. For both groups, the fMRI task evoked activation at mid-line prefrontal and retrosplenial cortices. TBI patients exhibited greater signal change in the anterior cingulate, precuneus and right temporal pole. Subsequently, a linear regression analysis was conducted for the TBI group, with the PCRS and a measure of cognitive speed entered as predictor variables to determine the selective effect of insight on self-evaluative brain activation. A more accurate level of trait/ability-based insight was related to increased signal change in the right anterior dorsal prefrontal cortex (PFC). The results suggest that one's post-injury level of self-referential insight is related to a network inclusive of the medial and right dorsal PFC.     

The head that wears the crown: Henry VIII and traumatic brain injury

Henry VIII of England is one of the most controversial figures in European history. He was born on 28 June 1491 as the second son of Henry VII and Elizabeth of York and became the heir to the English throne after his elder brother died prematurely. A contradictory picture of Henry’s character emerges from history: the young Henry was a vigorous, generous and intelligent king who saw early military and naval successes. In contrast, in his later years he became cruel, petty and tyrannical. His political paranoia and military misjudgements are in direct contrast to his earlier successes and promise. Several hypotheses have been put forward regarding his transformation from a renaissance king to a later medieval tyrant, including endocrinopathies, psychiatric illnesses and traumatic brain injury. In this paper we examine the historical evidence linking the change in Henry’s personality and health problems to traumatic brain injury. To our knowledge this is the first systematic neurological study of traumatic brain injury in Henry VIII.     

Cerebellar atrophy after severe traumatic head injury in children

Object: The purpose of this study was to describe late neuropathological MRI findings in pediatric severe head injury and to explore the relationship between these lesions and cognitive sequelae. Methods: Thirteen infants with severe head trauma (Glasgow 6) were included in this investigation. Clinical examination, a battery of tests designed to assess neurophysiological status, and MRI investigations of the brain were obtained in periods ranging between 8 and 20 months after the accident. Hemosiderin deposits, encephalomalacia, and cerebellar atrophy were the most frequent traumatic sequelae. The lesions were located in frontal lobes, the basal ganglia, and the cerebellum. Six patients had cerebellar atrophy associated with frontal or temporal postraumatic lesions. Cerebellar clinical dysfunction was observed in only 3 of these patients. Performance on tests evaluating frontal lobe functions was depressed in 5 of them. Conclusions: Late MRI after severe head trauma in our pediatric population showed unexpected cerebellar atrophy. Its correlation with prefrontal dysfunction is difficult to confirm because of its association with other parenchymal post-traumatic lesions. Further research involving a larger sample of patients with brain injury of varying severity is in progress, to investigate whether cerebellar atrophy could be a consequence of severe head trauma. Received: 25 May 2000 Revised: 4 July 2000     

Identity,grief and self-awareness after traumatic brain injury

The objective of this study was to investigate perceived identity change in adults with traumatic brain injury (TBI) and explore associations between identity change, grief, depression, self-esteem and self-awareness. The participants were 29 adults with TBI who were being followed up by a community brain injury rehabilitation service. Participants were longer post-injury than those more commonly studied. Time since injury ranged from 2.25 to 40 years (mean?=?11.17 years, SD?=?11.4 years). Participants completed a battery of questionnaires. Significant others and clinicians completed a parallel version of one of these measures. Questionnaires included the Head Injury Semantic Differential Scale (HISDS-III), Brain Injury Grief Inventory (BIGI), Hospital Anxiety and Depression Scale – Depression, Rosenberg Self-Esteem Scale (RSES) and the Awareness Questionnaire (Self/Significant other/Clinician versions). The main findings were that participants reported significant changes in self-concept with current self being viewed negatively in comparison to pre-injury self. Perceived identity change was positively associated with depression and grief and negatively associated with self-esteem and awareness. Awareness was negatively associated with self-esteem and positively associated with depression. These findings were consistent with previous research, revealing changes in identity following TBI. Further research is needed to increase our understanding of the psychological factors involved in emotional adjustment after TBI and to inform brain injury rehabilitation interventions, including psychotherapy approaches.