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

癫痫是世界上最常见的神经系统疾病之一，在大约675，000名美国人中仍然控制不佳，仅在美国每年花费125亿美元。尽管几十年来药物和器械治疗取得了进展，但我们仍然对如何根据个体患者中已知或疑似的癫痫发生机制定制治疗知之甚少。许多证据表明，异常的皮层连接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）不仅有可能探测，而且还调制皮质过度兴奋和功能连接在一个安全的和实验控制的方式。识别合适的靶点对TMS至关重要，但对于非病灶性或因异质性损伤而获得性癫痫的患者来说很困难。因此，发育畸形，如脑室周围结节性异位症（PNH）已作为癫痫发生的重要模型障碍，因为他们的异常，但容易表征的大脑结构。 在这个项目中，我们将使用先进的脑成像，生理和刺激为基础的技术在人类受试者与PNH和匹配的控制，以实现三个主要目标：1）我们将映射异常电路在PNH，似乎连接错位的灰质结节与覆盖皮层在这种情况下。利用弥散张量纤维束成像和静息态功能连接性磁共振成像（fcMRI），我们将确定PNH异位结节的离散皮质伴侣区域。2)我们将通过测量由单脉冲和成对脉冲TMS作为兴奋/抑制（E/I）平衡探针诱导的脑电图（EEG）电位，研究显示异常连接的局灶性脑区域内的皮质兴奋性。我们希望在正常皮层区域内表现出内在的过度兴奋，形成异常回路。3)最后，我们将采用TMS在一个连续的theta脉冲串协议，针对这些确定的皮层合作伙伴地区和匹配的控制目标，以确定在癫痫脑刺激的神经调节作用。特别是，我们将使用实验设计，包括两个功能性生物标志物（fcMRI和皮质E/I平衡）测量之前和之后的每个刺激会话，检查网络连接的影响和TMS的局部皮质效应。 难治性癫痫患者是一个异质性群体，具有局灶性皮质病变、异常神经回路和其他未确定的过度兴奋机制。最终，理想的治疗方法将需要临床医生根据具体确定的癫痫发生机制在个别患者中选择治疗，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、皮层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，并将对临床癫痫护理产生重大影响。

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.