Quantitative multimodal analyses in pediatric epilepsy surgery

描述(申请人提供)：这项研究的长期目标包括建立更通用的儿童新皮质癫痫手术标准，并借助对颅内脑电和神经成像数据的定量分析，以及利用体内定量多模式分析了解儿童新皮质癫痫的发作性癫痫放电的机制。这项提议的培训方面侧重于作为一名研究人员逐步走向独立。教育计划包括颅内脑电和神经成像定量分析的监督研究，以及在应用生物统计学、数据管理和研究伦理方面的正式培训和经验。五分之一的儿童癫痫在医学上是难以治愈的。一组患有难治性新皮质癫痫的儿童分别从推测的致痫区域手术中受益。然而，据报道，在患有额外颞叶癫痫的儿童中，通过各自的脑外科手术获得长期无癫痫发作的可能性低至50%。目的在正电子发射断层扫描(PET)上勾画畸形最近在我所取得了较好的手术效果(-80%无癫痫发作)，但这并不是最理想的。申请者假设癫痫大脑具有致痫能力的空间梯度，一些失败的手术可能是由于未完全切除致痫皮质，而成像研究和最佳脑电分析错过了这一点。致痫梯度的概念得到以下观察的支持：1)一些患者在切除推测的致痫区域数年后癫痫复发，包括神经影像异常和2)在明显成功的癫痫手术后停用抗癫痫药物导致三分之一的患者癫痫复发。由于脑电参数在脑内电极之间保持连续的值，我们将确定手术结果是否与手术未考虑的皮质神经生理异常的程度相关，并建立导致新皮质癫痫(包括癫痫痉挛)儿童最佳手术结果的临界值。癫痫发作在脑电上表现为持续的节律性发作性放电，其潜在机制尚不清楚。由于发作性放电通常表现为同步并传播到其他脑区，因此对分离的人脑组织进行体外分析可能不能代表整个癫痫回路。相反，利用颅内脑电和功能神经成像数据对新皮质部分性癫痫患儿的发作期脑电变化进行体内定量分析，将为发作期脑电的机制和临床意义提供不同的视角。最终，这些知识可能会为癫痫障碍带来更好的外科和药物治疗。如果获得资助，申请者将在良好的环境中获得必要的培训，以发展成为一名独立的调查人员。

DESCRIPTION (provided by applicant): The long-range objectives of this research include establishment of more universal criteria for neocortical epilepsy surgery in children, with the assistance of quantitative analysis of intracranial EEG and neuroimaging data, as well as understanding of the mechanisms of ictal epileptic discharges seen on EEG in pediatric neocortical epilepsy using in vivo quantitative multimodality analyses. The training aspects of this proposal focus on progression to independence as a researcher. The educational plan include supervised research in quantitative analyses of intracranial EEG and neuroimaging as well as formal training and experience in applied biostatistics, data management, and the ethical conduct of research. One-fifth of epilepsy in children is medically intractable. A subset of children with intractable neocortical epilepsy have benefited from respective surgery of the presumed epileptogenic zone. Yet, the chance of long-term seizure-free outcome by respective brain surgery is reported as low as 50% in children with extra temporal lobe epilepsy. Objective delineation of abnormalities on positron emission tomography (PET) imaging has recently yielded better surgical outcomes (-80% seizure-free) in our institute, but even this is not optimum. The applicant hypothesizes that an epileptic brain has a spatial gradient of epileptogenicity and that some of the failed surgery may have been due to the incomplete resection of epileptogenic cortex, which is missed by imaging studies and optimal EEG analysis. The concept of a gradient of epileptogenicity is supported by observations that 1) some patients experience seizure recurrence several years after resection of the presumed epileptogenic zone, including neuroimaging abnormalities and 2) discontinuation of antiepileptic drugs after apparently successful epilepsy surgery induce seizure recurrence in one-third of patients. Since EEG parameters retain continuous values among intracranial electrodes, we will determine whether surgical outcome is correlated with the degree of neurophysiological abnormalities in the cortex not respected by surgery, and establish the cutoff threshold resulting in the best surgical outcome in children with neocortical epilepsy (including epileptic spasms). Epileptic seizures are represented as sustained rhythmic ictal discharges on EEG, of which underlying mechanisms are unknown. Since ictal discharges typically show synchronization and propagation to other brain regions, in vitro analysis of isolated human brain tissues may not be representative of the entire epileptic circuitry. In contrast, in vivo quantitative analyses of ictal electrographic changes in children with neocortical partial seizures, using intracranial EEG and functional neuroimaging data will provide a different perspective regarding the mechanism and clinical significance of ictal discharges on the EEG. Ultimately, such knowledge may lead to better surgical and pharmaco-therapies for seizure disorders. If funded, the applicant will achieve the necessary training in an excellent environment to develop into an independent investigator.