Cortical connectivity, physiology, and response to stimulation in human epilepsy

描述（由申请人提供）：癫痫是世界上最常见的神经系统疾病之一，在大约67.5万美国人中仍然控制不佳，仅在美国每年就花费125亿美元。尽管几十年来药物和设备治疗取得了进步，但我们仍然对如何根据已知或怀疑的癫痫发生机制在个体患者中定制治疗知之甚少。许多证据表明，异常的皮质连通性在许多形式的癫痫中起作用，导致局部和网络脑功能的变化。非侵入性技术，如经颅磁刺激（TMS），不仅可以探测，而且可以以安全和实验控制的方式调节皮层的高兴奋性和功能连接。确定合适的靶点对经颅磁刺激至关重要，但对于非病变或因异质损伤而获得癫痫的患者却很困难。因此，脑室周围结节性异位（PNH）等发育性畸形由于其异常但易于表征的大脑结构而成为癫痫发生的重要模型障碍。在这个项目中，我们将使用先进的脑成像、生理和基于刺激的技术对PNH患者和匹配的对照组进行研究，以实现三个主要目标：1)我们将绘制PNH中的异常电路，该电路似乎在这种情况下将错位的灰质结节与覆盖的皮层连接起来。利用扩散张量束成像和静息状态功能连通性磁共振成像（fcMRI），我们将识别PNH异位结节的离散皮质伙伴区。2)我们将通过测量单脉冲和配对脉冲经颅磁刺激诱发的脑电图（EEG）电位，作为兴奋/抑制（E/I）平衡的探针，研究显示异常连通性的局灶性脑区域的皮质兴奋性。我们期望在形成异常回路的正常皮层区域内证明内在的超兴奋性。3)最后，我们将采用连续的θ波爆发方案，针对这些已确定的皮质伴侣区域和匹配的控制目标，以确定刺激在癫痫大脑中的神经调节作用。特别是，我们将使用实验设计来检查经颅磁刺激的网络连接效应和局部皮层效应，该实验设计包括在每次刺激之前和之后测量的两种功能性生物标志物（fcMRI和皮质E/I平衡）。顽固性癫痫患者是一个异质性的群体，具有局灶性皮质病变、异常的神经回路和其他未确定的高兴奋性机制。最终，理想的治疗方法将要求临床医生根据个别患者明确确定的癫痫发生机制选择治疗方法，使用对这些系统具有离散可测量影响的干预措施。我们在脑成像、皮质生理学和无创刺激方面的工作将在这一方向上取得新的进展，并将对临床癫痫治疗产生重大影响。

DESCRIPTION (provided by applicant): Epilepsy, one of the most common neurological conditions in the world, remains poorly controlled in about 675,000 Americans and costs $12.5 billion annually in the United States alone. Despite advances in drug and device therapy over several decades, we still have little understanding of how to tailor treatment based on known or suspected mechanisms of epileptogenesis in individual patients. Much evidence suggests that aberrant cortical connectivity plays a role in many forms of epilepsy, leading to changes in both local and network brain function. Noninvasive techniques such as transcranial magnetic stimulation (TMS) have the potential to not only probe but also modulate cortical hyperexcitability and functional connectivity in a safe and experimentally controlled manner. The identification of appropriate targets is critical for TMS, but difficult in patients who are nonlesional or have acquired epilepsy from heterogeneous insults. As a result, developmental malformations such as periventricular nodular heterotopia (PNH) have served as important model disorders for epileptogenesis because of their abnormal but readily characterized cerebral architecture. In this project we will use advanced brain imaging, physiological, and stimulation-based techniques in human subjects with PNH and matched controls, to accomplish three major goals: 1) We will map the abnormal circuitry in PNH that appears to connect misplaced gray matter nodules with the overlying cortex in this condition. Using diffusion tensor tractography and resting-state functional connectivity magnetic resonance imaging (fcMRI), we will identify discrete cortical partner regions for heterotopic nodules in PNH. 2) We will investigate cortical excitability within focal brain regions that show abnormal connectivity, by measuring electroencephalography (EEG) potentials induced by single- and paired-pulse TMS as a probe of excitation/inhibition (E/I) balance. We expect to demonstrate intrinsic hyperexcitability within regions of normal-appearing cortex that form aberrant circuits. 3) Finally, we will employ TMS in a continuous theta burst protocol, targeted at these identified cortical partner regions and matched control targets, to determine the neuromodulatory effects of stimulation in the epileptic brain. In particular, we will examine both network connectivity effects and local cortical effects of TMS using an experimental design that includes two functional biomarkers (fcMRI and cortical E/I balance) measured before and after each stimulation session. Patients with intractable seizures are a heterogeneous group with focal cortical lesions, aberrant neural circuitry, and other undetermined mechanisms of hyperexcitability. Ultimately, the ideal therapeutic approach will require clinicians to select treatment according to specifically identified epileptogenic mechanisms in individual patients, using interventions that have discretely measurable effects on these systems. Our work in brain imaging, cortical physiology, and noninvasive stimulation will make novel strides in this direction and will have a significant impact on clinical epilepsy care.