Quantitative multimodal analyses in pediatric epilepsy surgery

描述（由申请人提供）：本研究的长期目标包括通过颅内脑电图和神经影像学数据的定量分析，建立儿童新皮质癫痫手术更通用的标准，以及通过体内定量多模态分析了解儿童新皮质癫痫脑电图中癫痫发作的机制。该建议的培训方面侧重于作为一名研究人员的独立发展。教育计划包括颅内脑电图和神经成像定量分析的监督研究，以及应用生物统计学、数据管理和研究伦理行为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治性的。顽固性新皮质癫痫患儿的一个子集已经受益于各自的手术推定的癫痫区。然而，据报道，在颞叶外癫痫患儿中，通过相应的脑部手术获得长期无癫痫发作结果的机会低至50%。客观描述正电子发射断层扫描（PET）成像的异常最近在我们研究所产生了更好的手术结果（-80%无癫痫发作），但即使这也不是最佳的。申请人假设癫痫患者的大脑具有空间致痫性梯度，一些失败的手术可能是由于未完全切除致痫皮质，这是成像研究和最佳脑电图分析所遗漏的。致痫性梯度的概念得到以下观察结果的支持：1)一些患者在切除假定的致痫区数年后癫痫复发，包括神经影像学异常；2)在明显成功的癫痫手术后停用抗癫痫药物会导致三分之一的患者癫痫复发。由于脑电图参数在颅内电极间保持连续值，我们将确定手术结果是否与手术未考虑到的皮质神经生理异常程度相关，并建立导致新皮质癫痫（包括癫痫性痉挛）患儿最佳手术结果的切断阈值。癫痫发作在脑电图上表现为持续的节律性发作放电，其潜在机制尚不清楚。由于脑电图放电通常表现为同步并传播到其他脑区，因此对分离人脑组织的体外分析可能不能代表整个癫痫电路。相比而言，利用颅内脑电图和功能神经影像学数据对新皮层部分性癫痫患儿的发作期电图变化进行体内定量分析，将为发作期放电对脑电图的影响机制和临床意义提供不同的视角。最终，这些知识可能会导致更好的手术和药物治疗癫痫。如果获得资助，申请人将在一个良好的环境中完成必要的培训，发展成为一名独立的研究者。

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.