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

描述(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。尽管药物和设备治疗在过去几十年中取得了进展，但我们仍然对如何根据个别患者的已知或可疑的癫痫发生机制进行量身定制的治疗知之甚少。许多证据表明，异常的皮质连接在许多形式的癫痫中发挥作用，导致局部和网络大脑功能的改变。非侵入性技术，如经颅磁刺激(TMS)，不仅有可能探测，而且有可能以一种安全和实验控制的方式调节皮质的超兴奋性和功能连接。确定合适的靶点对于TMS来说是关键的，但对于非皮损性或因不同类型的侮辱而获得癫痫的患者来说很困难。因此，发育畸形，如脑室周围结节异位(PNH)，由于其异常但容易表现出的大脑结构特征，已成为癫痫发生的重要模式障碍。在这个项目中，我们将使用先进的脑成像、生理和刺激技术，在PNH患者和匹配的对照组中实现三个主要目标：1)我们将绘制PNH中似乎连接错位的灰质结节和覆盖的皮质的异常回路。使用扩散张量束成像和静息状态功能连接磁共振成像(FcMRI)，我们将确定PNH中异位结节的离散皮质配对区。2)我们将通过测量单脉冲和成对脉冲TMS诱发的脑电(EEG)电位作为兴奋/抑制(E/I)平衡的探针，来研究大脑局灶性连接异常区域的皮质兴奋性。我们希望在形成异常回路的正常皮质区域内表现出内在的超兴奋性。3)最后，我们将使用TMS在连续的theta Burst方案中，针对这些已识别的皮质配对区域和匹配的对照靶点，来确定刺激在癫痫脑中的神经调节效应。特别是，我们将使用包括两个功能生物标记物(fcMRI和皮质E/I平衡)的实验设计来研究TMS的网络连接效应和局部皮质效应。顽固性癫痫患者是一个异质性的群体，有局灶性皮质损害、异常的神经回路和其他未确定的过度兴奋机制。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致痫机制选择治疗方法，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、皮质生理学和非侵入性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。 公共卫生相关性：这个项目将研究癫痫脑畸形中异常的神经连接、皮质超兴奋性以及非侵入性磁刺激的神经调制效应，这将对我们理解癫痫障碍在人脑中的发展以及如何最好地治疗具有重要意义。从这项研究中获得的见解将为神经学家在评估失控癫痫患者时使用额外的、强大的工具，并将直接塑造创新治疗方式在医学难治性癫痫中的未来使用。

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. PUBLIC HEALTH RELEVANCE: This project, which will investigate aberrant neural connectivity, cortical hyperexcitability, and the neuromodulatory effects of noninvasive magnetic stimulation in an epileptic brain malformation, will have significant implications for our understanding of how seizure disorders develop in the human brain and how best to treat them. The insights gained from this research will lead to additional, powerful tools for neurologists to employ when evaluating patients with uncontrolled seizures, and will directly shape the future usage of innovative therapeutic modalities in medically refractory epilepsy.