Animal Models of Inherited Epilepsy

A significant proportion of the childhood epilepsies have a genetic component. Therefore, animal models that can be bred for seizure expression may provide important information regarding the mechanisms by which molecular defects result in the neuronal hyperexcitability states collectively termed “epilepsy.” Because of the rate and ease of breeding, rodent models are the most commonly used. The genetically epilepsy-prone rat has motor seizures in response to auditory stimuli. It is likely that the seizures are generated in the inferior colliclus because of an abnormality in the noradrenergic system. The seizure predisposition is inherited as an autosomal dominant trait. The genetic absence epilepsy rat has age-related spontaneous seizures characterized by motor arrest and head drops that are correlated with generalized spike-wave on the electroencephalogram (EEG). The seizure generating mechanism appears to be located in the lateral thalamic nuclei. The epileptic mongolian gerbil demonstrates behavioral arrest followed by myoclonic, tonic, and tonic-clonic seizures in response to unfamiliar environments. The underlying neuroanatomy involves hippocampal-cortical interactions indicative of a partial epilepsy. The tottering mouse has absence and myoclonic seizures, a 6- to 7-Hz ictal spike-wave EEG, and noradrenergic hyperinnervation that are linked to a mutation on chromosome 8. Hippocampal network hyperexcitability has been found with normal neuronal intrinsic properties. Stargazer is a mouse mutant with almost identical clinical and electrographic features as found in tottering. However, the genetic defect is located on chromosome 15 and no abnormalities of norepinephrine have been discovered. The El mouse demonstrates ictal automatisms in response to vestibular stimulation. Metabolic and structural abnormalities have been found in the hippocampus. Linkage to chromosomes 9 and 2 have been reported recently. The dilute brown agouiti mouse demonstrates motor seizures in response to auditory stimuli. Chromosomes 4 and 17 are linked to seizure expression. Thus, a variety of models exist to study the genetic, biochemical, structural and electrophysiological mechanisms that underlie the predisposition and expression of the inherited epilepsies.     

Magnetic Resonance Imaging of Functional Anatomy: Use for Small Animal Epilepsy Models

Summary:  Neuroimaging has greatly assisted the diagnosis and treatment of epilepsy. Volumetric analysis, diffusion-weighted imaging, and other magnetic resonance imaging (MRI) modalities provide a clear picture of altered anatomical structures in both focal and nonfocal disease. More recently, advances in novel imaging methodologies have provided unique insights into this disease. Two examples include manganese-enhanced MRI (MEMRI) and diffusion tensor imaging (DTI). MEMRI involves injection of MnCl₂ to evaluate neuronal activity where it is actively transported. Areas of neuronal hyperactivity are expected to have altered uptake and transport. Mapping of activation along preferential uptake pathways can be confirmed by T₁-weighted imaging. DTI uses the intrinsic preferential mobility of water movement along axonal pathways to map anatomical regions. DTI has been used to investigate white matter disease and is now being applied to clinical and, to a lesser extent, animal investigations of seizure disorders. These two diverse MRI methods can be applied to animal models to provide important information about the functional status of anatomical regions that may be altered by epilepsy.     

颞叶癫Xian术前综合定位诊断

目的:研究术前对颞叶癫癎不同定位手段的综合应用。方法:采用ＥＥＧ、ＰＥＴ、ＭＲＩ、ＭＲＳ对２４例顽固性颞叶癫癎患者进行术前定位。结果:结合ＥＥＧ,ＭＲＩ,ＭＲＳ,ＰＥＴ对８３%,７９%,８５%病例作出定位;ＥＥＧ结合ＭＲＩ与ＭＲＳ,可对９２%病例作出定位;ＥＥＧ结合ＭＲＩ,ＭＲＳ,ＰＥＴ,可对９６%的病例作出定位。结论:结合ＥＥＧ,综合采用ＭＲＩ,ＭＲＳ,ＰＥＴ等手段可提高对颞叶癫癎术前定位的准确率。     

Positron Emission Tomography in Basic Epilepsy Research: A View of the Epileptic Brain

Summary:  The neurobiological processes that result in epilepsy, known as epileptogenesis, are incompletely understood. Moreover, there is currently no therapy that effectively halts or impedes the development or progression of the condition. Positron Emission Tomography (PET) provides valuable information about the function of the brain in vivo, and is playing a central role in both clinical practice and research. This technique reliably reveals functional abnormalities in many epilepsy syndromes, particularly temporal lobe epilepsy. Unfortunately, epileptogenesis is extremely difficult to study in human patients who usually present with established epilepsy, rather than at the early stages of the process. Animal models offer the advantage of permitting the assessment of the pre-, developing, and chronic epileptic states. However, traditional techniques (e.g., histology) are only able to examine the brain at one time point during epileptogenesis in any one individual. Recent advances in dedicated small animal PET (saPET) allow researchers for the first time to study in vivo biomolecular changes in the brain during epileptogenesis by means of serial acquisitions in the same animal. Repeated application of in vivo imaging modalities in the same animal also decreases the effect of biological inter-individual variability and the number of animals to be used. The availability of novel PET tracers permits the investigation of a broad range of biochemical and physiological processes in the brain. Besides research on epileptogenesis, saPET can also be applied to investigate in vivo the biological effect of novel treatment strategies. saPET is widely used in many fields of pathophysiological investigation and is likely to significantly enhance epilepsy research.     

Coupling of Cortical and Thalamic Ictal Activity in Human Partial Epilepsy: Demonstration by Functional Magnetic Resonance Imaging

Summary: Purpose: To localize metabolic coupling between a cortical seizure focus and other brain regions by using functional magnetic resonance imaging (fMRI) data of ictal events obtained in a patient with frequent partial seizures involving his right face.
Methods: Cross-correlation analysis was used to examine time-dependent alterations in regional signal intensity that correlated with signal-intensity changes from a well-characterized cortical seizure focus in a patient with frequent partial seizures.
Results: Signal changes in the left ventrolateral thalamus showed a high degree of temporal correlation with signal changes in the left frontal cortical seizure focus, demonstrating close corticothalamic coupling of metabolism.
Conclusions: A significant role for thalamocortical interactions in the pathophysiology of epilepsy has been suggested by studies in animal models and human patients. This finding provides further support for the integral involvement of the thalamus in human focal epilepsy and underscores the potential for identifying neuronal networks by using cross-correlation analysis of fMRI data.     

3，5-二羟苯甘氨酸致痈模型的研究进展

癫痫动物模型是研究癫痫发病机制和药物靶点的重要工具。3,5-二羟苯甘氨酸（DHPG）是近年来发现的一种新的化学致痫剂，在离体脑片及整体动物上均能诱导出癫痫样活动，本文对有关DHPG诱导癫痂动物模型的研究进展作一综述。     

Multimodal MR Imaging: Functional, Diffusion Tensor, and Chemical Shift Imaging in a Patient with Localization-Related Epilepsy

PURPOSE: To demonstrate the integration of complementary functional and structural data acquired with magnetic resonance imaging (MRI) in a patient with localization-related epilepsy. METHODS: We studied a patient with partial and secondarily generalized seizures and a hemiparesis due to a malformation of cortical development (MCD) in the right hemisphere by using EEG-triggered functional MRI (fMRI), diffusion tensor imaging (DTI), and chemical shift imaging (CSI). RESULTS: fMRI revealed significant changes in regional blood oxygenation associated with interictal epileptiform discharges within the MCD. DTI showed a heterogeneous microstructure of the MCD with reduced fractional anisotropy, a high mean diffusivity, and displacement of myelinated tracts. CSI demonstrated low N-acetyl aspartate (NAA) concentrations in parts of the MCD. CONCLUSIONS: The applied MR methods described functional, microstructural, and biochemical characteristics of the epileptogenic tissue that cannot be obtained with other noninvasive means and thus improve the understanding of the pathophysiology of epilepsy.     

EEG Monitoring during Functional MRI in Animal Models

Summary:  Despite its excellent temporal resolution, electroencephalogram (EEG) has poor spatial resolution to study the participation of different brain areas in epileptic discharges, and the propagation of seizures to subcortical areas is not revealed. Furthermore, EEG provides no information about metabolic changes that occur in the brain before and during the epileptic discharges. Thus, monitoring variations in blood flow and oxygenation in response to epileptic discharges can provide additional complementary information. Functional magnetic resonance imaging (fMRI) technology can be used to study the hemodynamic changes associated with interictal epileptiform discharges or epileptic seizures (i.e., before, during or after them) in experimental animal models and may noninvasively monitor these changes over time. Blood oxygenation level-dependent fMRI has superior spatial resolution compared with other functional imaging modalities and utilizes changes in local magnetic field properties to measure the amount of deoxyhemoglobin in each brain areas as an indicator of brain activity. Simultaneous recording of EEG and fMRI is required to achieve this objective. This article describes methods of acquiring and monitoring EEG during fMRI studies in experimental animals. Particular attention will be paid to methods used to eliminate artifacts induced in the acquired magnetic resonance images by EEG equipment and MR-related artifacts in EEG recordings.     

Magnetic Resonance Imaging in Animal Models of Epilepsy—Noninvasive Detection of Structural Alterations

Summary:  Small animal magnetic resonance imaging (MRI) has opened a window through which brain abnormalities can be observed over time in rodents noninvasively. We review MRI studies done during epileptogenesis triggered by status epilepticus in rat. Most of these studies have used quantitative T2, diffusion, and/or volumetric MRI. The goal has been to identify the distribution and severity of structural lesions during the epileptogenic process, that is, soon after status epilepticus, during epileptogenesis, and after the appearance of spontaneous seizures. Data obtained demonstrate that MRI can be used to associate the development of brain pathology with the evolution of clinical phenotype. MRI can also be used to select animals to preclinical studies based on the severity and/or distribution of brain damage, thus making the study population more homogeneous, for example, for assessment of novel antiepileptogenic or neuroprotective treatments. Importantly, follow-up data collected emphasize interindividual differences in the dynamics of development of abnormalities that could have remained undetected in a typical histologic analysis providing a snapshot to brain pathology. A great future challenge is to take advantage of interanimal variability in MRI in the development of surrogate markers for epilepsy or its comorbidities such as memory impairment. Understanding of molecular and cellular mechanisms underlying changes in various MRI techniques will help to better understand complex progressive pathological processes associated with epileptogenesis and epilepsy.     

颞叶癫癎弥散张量成像的影像学特征

颞叶癫癎（TLE）作为常见的一类局限性癫癎,了解其颅内病灶至关重要。MR弥散张量成像是一种水弥散成像技术,能够反映白质纤维的解剖和病理过程。本文介绍了TLE在弥散张量成像中的影像学表现：TLE患者病灶侧海马,与致癎灶相关连接结构如穹窿、扣带回、胼胝体和额颞叶联系纤维在弥散张量成像中均有异常信号,另外在双侧丘脑、额枕叶、双侧小脑亦有异常信号发现。TLE患者颅内各类白质纤维的信号异常与患者的某些认知功能有关。     

210例癫（痫）患者脑电图及头颅磁共振成像检查结果分析

目的 探讨头颅磁共振成像（MRI）和脑电图在癫（痫）诊断中的应用以及两者的相关性.方法 回顾性分析210例中国宁夏回族自治区农村癫（痫）患者的一般病例资料、脑电图及头颅MRI检查结果.结果 210例癫（痫）患者中,头颅MRI发现异常139/210例（66.2％）,以软化灶、脱髓鞘病变为主.脑电图异常180/210例（85.7％）,其中轻度异常66/180例（36.7％）,中度异常为106/180例（58.9％）,重度异常为8/180例（4.4％）.脑电图异常组（68.9％）患者的头颅MRI异常发现率明显高于脑电图正常组患者（50.0％）,差异有统计学意义（P=0.043）.结论 脑电图是确诊癫（痫）和指导治疗的有利依据,头颅MRI为癫（痫）病因诊断的首选影像学检查手段,两者有一定关联.     

颞叶癫患者的头颅磁共振显像异常表现分析

目的对颞叶癫(TLE)患者头颅磁共振成像(MRI)异常表现进行分析,为临床诊治TLE提供参考。方法对56例TLE患者的头颅MRI异常表现进行分析总结。结果 56例TLE患者头颅MRI主要表现为海马硬化、颞叶软化灶、颞叶肿瘤、颞叶皮质萎缩等。其中,颞叶肿瘤类型多样,主要为少突胶质瘤、星形细胞瘤、脑膜瘤。结论 TLE患者头颅MRI异常表现复杂多样,正确掌握其特点有助于TLE的诊治。     

Hemodynamic and Metabolic Aspects of Photosensitive Epilepsy Revealed by Functional Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy

PURPOSE: To study in humans the hemodynamic and metabolic consequences of both photic stimulation-triggered and spontaneous generalized epileptiform discharges. METHODS: Simultaneous EEG, functional magnetic resonance imaging (fMRI) and MR spectroscopy were performed in a 1.5-T scanner in 16 patients with generalized epilepsy, including nine with photosensitive epilepsy, and 12 normal subjects. RESULTS: With a flash stimulation duration of 2 s, prominent visual cortex activation was seen in all normals and patients. There were no fMRI-registered hemodynamic abnormalities found in relation to the brief photoparoxysmal spike-wave activity evoked in the photosensitive patients. However, irrespective of the presence of a spike-wave response to the photic stimulation, the photosensitive patients showed four unique findings compared with normals: (a) slightly, but significantly, increased lactate levels in the occipital cortex in the resting state, (b) an increased area of visual cortical activation with photic stimulation, (c) simultaneous with the occipital cortex stimulus-induced increased fMRI signal there were noncontiguous areas of signal attenuation most prominent in perirolandic regions, and (d) a marked decrement (undershoot) of fMRI signal intensity immediately after the photic stimulation in the occipital cortex and in the region of the posterior cingulate gyrus. CONCLUSIONS: These findings suggest abnormal interictal metabolism and increased vascular reactivity in the photosensitive patients.     

Clinical Usefulness of Simultaneous Electroencephalography and Functional Magnetic Resonance Imaging in Children With Focal Epilepsy

Background and PurposeThe current study analyzed the interictal epileptiform discharge (IED)-related hemodynamic response and aimed to determine the clinical usefulness of simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI) in defining the epileptogenic zone (EZ) in children with focal epilepsy.MethodsPatients with focal epilepsy showing IEDs on conventional EEG were evaluated using EEG-fMRI. Statistical analyses were performed using the times of spike as events modeled with multiple hemodynamic response functions. The area showing the most significant t-value for blood-oxygen-level-dependent (BOLD) changes was compared with the presumed EZ. Moreover, BOLD responses between -9 and +9 s around the spike times were analyzed to track the hemodynamic response patterns over time.ResultsHalf (n=13) of 26 EEG-fMRI investigations of 19 patients were successful. Two patients showed 2 different types of spikes, resulting in 15 analyses. The maximum BOLD response was concordant with the EZ in 11 (73.3%) of the 15 analyses. In 10 (66.7%) analyses, the BOLD response localized the EZs more specifically. Focal BOLD responses in the EZs occurred before IEDs in 11 analyses and were often widespread after IEDs. Hemodynamic response patterns were consistent in the same epilepsy syndrome or when repeating the investigation in the same patients.ConclusionsEEG-fMRI can provide additional information for localizing the EZ in children with focal epilepsy, and also reveal the pathogenesis of pediatric epilepsy by evaluating the patterns in the hemodynamic response across time windows of IEDs.     

Imaging and in vivo quantitation of beta-amyloid: an exemplary biomarker for Alzheimer's disease?

Alzheimer's disease (AD) is characterized pathologically by the presence of beta-amyloid plaques in the brain. A substantial body of research indicates that the presence of increased beta-amyloid peptide (Abeta) is neurotoxic and may initiate the further pathology observed in AD, including neurofibrillary tangles, synaptic loss and dysfunction, and neurodegeneration. The use of brain imaging in patients with or at risk for AD has increased our understanding of the pathophysiology of the disease and may potentially aid in diagnosis. The development of new therapeutics that reduce Abeta in the brain has also indicated a potential use for amyloid imaging in monitoring response to treatment. This review explores the utility of amyloid as a biomarker and the use of positron emission tomography and magnetic resonance imaging in the diagnosis and treatment of AD.     

Magnetic Resonance Imaging Evaluation of Focal Computed Tomography Abnormality in Epilepsy

Sixty-seven patients with epilepsy and isolated enhancing computed tomography (CT) scan lesion were studied with magnetic resonance imaging (MRI). Fifty-six patients (83.5%) had partial seizures and 11 (16.4%) had generalized seizures. Four distinct groups were identified by MRI: nonspecific 16 cases (23.8%), tuberculoma 38 cases (56.7%), cysticercosis 12 cases (17.9%), and abscess 1 case (1.4%). Patients in the non-specific group had lesions that were hyperintense on T2 images and hypointense or isointense on T1 images. Such lesions resolved completely in 5 months with serial MRIs while the patients were receiving antiepileptic drugs (AEDs). Virologic studies, including cerebrospinal fluid (CSF) serology, are suggested for patients with such MRI lesions.