GABAB受体对大鼠海马CA1区锥体细胞突触传递的作用

目的研究激活GABA_B受体对大鼠海马CA1区锥体细胞突触传递的影响。方法对成年大鼠海马脑片CA1区锥体细胞采用“盲法”全细胞电压钳记录,分别检测和分析巴氯芬(10μmol/L)对自发性的兴奋性突触后电流(EPSCs)和抑制性突触后电流(IPSCs)的影响。结果巴氯芬可显著降低符氨酸能EPSCs和γ-氨基丁酸能IPSCs的频率(P＜0．01),各自达58%±7%(n=17)和42%±10%(n=15),而对它们的幅度无显著性影响。结论巴氯芬对海马CA1区锥体细胞EPSCs和IPSCs的抑制作用属于突触前抑制,推测GABA_B受体所介导的这种抑制作用对CA1区神经元兴奋性的传出具有抑制作用,从而对癫痫的产生有控制作用。     

单侧液压脑损伤对大鼠双侧海马GFAP表达和CA1区突触传递的影响

目的研究单侧液压脑损伤(FPI)对大鼠双侧海马区胶质纤维酸性蛋白(GFAP)表达和CA1区突触传递的影响。方法建立大鼠单侧液压脑损伤模型,脑标本分为对照组(包括正常对照和假手术对照)、FPI损伤同侧组和FPI损伤对侧组。免疫组化法检测海马水平切片GFAP表达,对海马CA1区锥体神经元进行细胞内记录。结果FPI大鼠双侧海马齿状回门区和CA1区GFAP表达均比对照组明显增强。FPI损伤同侧组兴奋性输入-输出关系曲线的斜率比其他两组显著增大(P<0.05);FPI损伤同侧组和对侧组双脉冲易化(PPF)比值和抑制性突触后电位(IPSP)幅值均比对照组显著减小(P<0.05);FPI损伤同侧组和对侧组双脉冲抑制(PPD)比值均比对照组显著增大(P<0.05)。结论大鼠单侧液压脑损伤对双侧海马均可产生影响,导致双侧海马CA1区兴奋性突触传递增强,抑制性突触传递减弱。     

成年小鼠癫痫发作早期突触内、外N-甲基-D-天冬氨酸受体介导的电流变化

在癫痫疾病的发生和反复发作的过程中,N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体（NMDA受体）起着重要的作用。近年来的研究发现,突触内和突触外的NMDA受体在包括突触可塑性和细胞死亡的信号通路中起着不同的甚至是截然相反的作用。因此,我们在本研究中探讨了突触内、外NMDA受体介导的兴奋性突触后电流在癫痫发病的病理过程中的变化。我们利用氯化锂联合匹罗卡品（pilocarpine, PILO）诱导了成年癫痫小鼠模型,并在癫痫发作24小时后制作了急性海马切片,利用膜片钳全细胞记录法对CA1区锥体神经元的突触内、外NMDA受体电流进行了记录。我们发现,1）突触内NMDA受体电流的上升时间及衰减时间与对照组比较均无统计学差异;2）突触外NMDA受体电流的兴奋性电流峰值、面积峰值比、以及上升时间亦无统计学差异;3）但突触外电流的衰减时程相对于对照组加快。以上结果提示突触外NMDA受体可能参与癫痫的发病机制。     

颞叶癫痫大鼠海马CA1区突触可塑性与空间记忆能力关系的研究

目的探讨颞叶癫痫大鼠海马CA1区突触超微结构与空间记忆能力改变的关系。方法以海人酸杏仁核微量注射建立经典的雄性Wistar大鼠颞叶癫痫化学点燃模型,分别于点燃后11d、17d、21d测定大鼠的空间记忆能力,并观察第21d海马CA1区神经毡突触超微结构变化。结果颞叶癫痫大鼠空间记忆能力减低,同时伴有海马CA1区神经毡内突触数密度降低(P<0．05),突触活性区膜面积缩小(P<0．05),突触界面曲率降低(P< 0．05),比表面减小(P<0．05),突触小泡数密度降低(P<0．05)。结论颞叶癫痫大鼠海马CA1区神经毡内突触损害和活力可能是导致其空间记忆能力下降的重要机制。     

荧光金逆行示踪观察匹罗卡品致痫大鼠CA1区锥体细胞突触联系变化的研究

目的通过荧光金(FG)逆行示踪观察氯化锂-匹罗卡品致痫模型大鼠慢性自发发作期海马CA1区锥体细胞之间的突触联系变化。方法 SD大鼠2 0只随机分为实验组和对照组。癫痫持续状态后6 0 d左右,利用立体定位仪在活体内注射逆行性示踪剂FG至海马CA1区,术后常规喂养5~7 d后灌注取材。激光扫描共聚焦显微镜下观察FG的分布。结果 7只实验组大鼠中有5只可见有FG标记的锥体细胞,对照组未见。实验组中有2只大鼠在海马下托亦可见有FG标记的锥体细胞,而对照组未见。结论颞叶癫痫大鼠海马CA1区锥体细胞之间和下托至CA1区有异常兴奋性突触联系,其可能是构成异常兴奋性回路的解剖学基础。     

外伤后癫痫大鼠脑内突触素和苔藓纤维的观察

目的 通过研究液压脑损伤后突触索和苔藓纤维在外伤后癫痫和非癫痫的大鼠脑内的不同变化,以探讨外伤后癫痫的发病机制.方法 应用液压脑损伤复制脑损伤动物模型并记录脑电图和行为学变化,3个月后应用突触素免疫组织化学、Timm染色和汁算机图像分析技术分析皮质区突触索及海马区苔鲜纤维的不同变化.结果 突触素在皮质损伤区表达癫痫组(n=11)高于非癫痫组(n=20,P<0.05),苔藓纤维出芽在癫痫组CA3区始层明显增多(P<0.05).结论 突触素的表达增强和苔藓纤维出芽与外伤后癫痫天系密切,因果关系有待进一步研究.     

尼莫地平对癫痫大鼠学习记忆及海马超微结构的影响

目的探讨尼莫地平(nimodipin,NIM)对戊四氮(pentylenetetrazol,PTZ)点燃癫痫大鼠学习记忆能力及海马CA3区超微结构的影响。方法动物分为正常对照组、PTZ组和NIM PTZ组,采用PTZ慢性点燃癫痫模型,应用Morris水迷宫观察各组大鼠空间学习记忆能力,电镜观察海马CA3区突触界面结构,并对突触活性参数量化分析。结果PTZ点燃癫痫大鼠存在学习记忆能力下降,其海马CA3区突触后致密物显著变薄、突触小泡显著减少、突触间隙显著增宽(P<0.05);尼莫地平能改善癫痫大鼠学习记忆障碍,与PTZ组比较,突触后致密物增厚、突触小泡增多、突触间隙变窄(P<0.05)。结论PTZ点燃癫痫大鼠存在空间学习记忆受损,可能与突触界面参数改变有关;NIM可以改善癫痫大鼠突触超微结构,提高学习记忆能力。     

癫痫大鼠海马CA3区钙超载与癫痫发病机制的相关性研究

目的:探讨癫痫的发病机制,海马CA3区钙超载是否在癫痫的发病机制中起主要作用。方法:用荧光倒置显微镜来测定癫痫状态下海马CA1、CA3区钙超载的情况,并用钙离子拮抗剂尼莫地平作用于海马脑片看钙超载的变化。并把点燃成功的大鼠麻醉后做海马脑片,看海马的组织病理学改变。结果:癫痫大鼠海马CA1、CA3区钙超载高于对照组,CA3区钙超载高于CA1区,在尼莫地平的作用下CA3区钙超载明显降低。组织病理学改变亦显示CA3区是神经元变性、坏死是海马区最明显的部位。结论:钙超载参与了癫痫的发病机制,其中海马CA3区的钙超载在癫痫发病机制中起主要作用。     

慢性应激抑郁大鼠海马CA1神经元突触可塑性研究

目的 探讨慢性轻度不可预见应激(chronic unpredictable mild stress,CUMS)抑郁模型大鼠海马CA1区神经元的突触可塑性改变.方法 将20只雄性Sprague-Dawley (SD)大鼠随机等分为CUMS组和对照组,前者连续28天每天随机接受不同的应激,对照组同样条件下饲养但不给应激,至第28天进行行为测评后处死,在日立(H7500)透射电镜下测量海马CA1神经元突触界面结构参数.结果 CUMS抑郁大鼠海马CA1神经元突触活性区长度(216.64±20.19 nm)及突触后致密物厚度(42.4±5.23 nm)显著小于对照组(321.58±12.27nm,69.6±4.77 nm),差异有统计学意义(P＜0.05),突触界面曲率及宽度与对照组差异无统计学意义(P＞0.05).结论 慢性应激性抑郁大鼠存在海马CA1区神经元突触可塑性的改变.这提示抑郁症的发病机制可能与海马神经元突触可塑性相关.     

戊四氮点燃大鼠海马CA3区钙超载与亚低温对点燃大鼠脑保护作用的研究

目的 海马CA1区钙超载是否在癫痫的发病机制中起主要作用及亚低温对癫痫是否有治疗意义。方法用荧光倒置显微镜来测定癫痫状态下海马CA1、CA3区钙超载的情况，并用钙离子拮抗剂尼莫地平作用于海马脑片看钙超载的变化。然后将大鼠分为头皮温度为41℃、37℃、32℃、26℃的4组，通过对4组点燃大鼠行为学和海马组织病理学的观察来看亚低温对癫痫的脑保护作用。结果癫痫大鼠海马CA1，CA3区钙超载高于对照组．CA1区钙超载高于CA1区。在尼莫地平的作用下CA1区钙超载明显降低。组织病理学改变显示CA1区是海马区神经元变性、坏死最明显的部位。而亚低温下癫痫的发作程度和神经元变性、坏死最轻。结论钙超载参与了癫痫的发病机制，其中海马CA3区的钙超载在癫痫发病机制中起主要作用。而亚低温对脑有保护作用。     

Epilepsy and anomalies of neuronal migration: MRI and clinical aspects

Neuronal migration disorders are the result of disturbed brain development. In such disorders, neurons are abnormally located. In diagnosing these conditions, magnetic resonance imaging is superior to any other imaging technique. This enables us to improve our knowledge of the clinical correlates of neuronal migration. With reference to migrational disorder, a retrospective study of all 303 patients with epileptic seizures referred for magnetic resonance imaging during a 3-year period was performed, 13 patients (aged 12-41, mean age 27) were identified. They represent 4.3% of the entire study group. Of the patients with known epilepsy, 6.7% and of the mentally retarded, 13.7% had migrational disorders. Four patients had schizencephaly as the dominant finding, one was classified as hemimegalencephaly, 2 had isolated heterotopias, and 6 had localized pachy- and/or poly-microgyria. The clinical pictures are complex. Ectopias of grey matter are recognised foci of epilepsy, but from an epileptological and a clinical viewpoint little attention has been given to these disorders. The present study shows that malmigration is not rare in epilepsy patients, especially not in the mentally retarded.     

Hepatic Considerations in the Use of Antiepileptic Drugs

Summary: Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.     

Vascular Malformations and Epilepsy: Clinical Considerations and Basic Mechanisms

Summary: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.     

Classification of methods in transcranial Electrical Stimulation (tES) and evolving strategy from historical approaches to contemporary innovations

Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.     

Carbamazepine Efficacy and Utilization in Children

Summary: Carbamazepine is effective for preventing partial and generalized tonic-clonic seizures in children. Although absence epilepsies are more common in children than adults, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to carbamazepine. The differential diagnosis of ictal staring is an especially important issue in children because absence and atypical absence seizures are more prevalent in children than adults. Age-related pharmacokinetic differences and drug interactions are major considerations in children. On average, children have higher clearance rates of carbamazepine, shorter half-lives, and higher ratios of carbamazepine-10, 11-epoxide to carbamazepine than adults. In addition, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions. When carbamazepine is administered along with valproate, drug protein binding interactions can cause intermittent side effects.     

Neonatal Seizures: Problems in Diagnosis and Classification

Summary: The clinical identification of neonatal seizures is critical for the recognition of brain dysfunction; however, diagnosis is often difficult because of the poorly organized and varied nature of these behaviors. Current classification systems are limited in their ability to communicate motor, autonomic, and electroencephalo-graphic features of seizures precisely and to provide a basis for uniform effective diagnosis, therapy, and determination of prognosis. Recent investigations of neonates, utilizing bedside electroencephalographic/polygraphic/ video monitoring techniques, have provided the basis for improved diagnosis and classification of seizures in the newborn. These studies have demonstrated that not all clinical phenomena currently considered to be seizures require electrocortical epileptiform activity for their initiation or elaboration. In addition, the specific clinical character of the phenomena considered to be seizures, the clinical state of the infant, and the character of the EEG indicate the probable pathophysiological mechanisms involved and suggest probable etiologies, prognosis, and therapy. Similarities between animal models that demonstrate reflex physiology and neonates with motor automatisms and tonic posturing suggest that these clinical behaviors may not be epileptic in origin but, rather, primitive movements of progression and posture mediated by brainstem mechanisms. Although not all clinical behaviors currently considered to be neonatal seizures may have similar pathophysiological mechanisms, they are clinically significant because they all indicate brain dysfunction.     

Valproate Monotherapy in the Management of Generalized and Partial Seizures

Summary: For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.     

Un nouveau cadre conceptuel de travail pour la psychiatrie

In an attempt to place psychiatric thinking and the training of future psychiatrists more centrally into the context of modern biology, the author outlines the beginnings of a new intellectual framework for psychiatry that derives from current biological thinking about the relationship of mind to brain. The purpose of this framework is twofold. First, it is designed to emphasize that the professional requirements for future psychiatrists will demand a greater knowledge of the structure and functioning of the brain than is currently available in most training programs. Second, it is designed to illustrate that the unique domain which psychiatry occupies within academic medicine, the analysis of the interaction between social and biological determinants of behavior, can best be studied by also having a full understanding of the biological components of behavior.