Precise, non-invasive, axon-sparing surgery for the treatment of drug resistant epilepsy

项目概要： 耐药性癫痫（DRE）仍然是一个艰巨的生物医学挑战，影响 大约三分之一新治疗的癫痫病例。受 DRE 影响的个人质量较差 生命，并可能面临危及生命的并发症。手术切除致癫痫组织可以显着 减少癫痫发作并提高生活质量。然而，癫痫手术可能具有高度侵入性，可能会产生 损伤不限于目标组织，并且在大脑的某些关键区域是不可行的。另外， 与目标不相符并影响邻近组织的手术损伤可能会产生长期的损伤。 术语功能缺陷。最后，目标组织的不完全切除或消融可能导致癫痫发作不良 管理。该提案的目的是开发和测试一种非侵入性、有针对性、适形的手术 优化癫痫控制的策略，扩大适合手术干预的癫痫类型， 最终，改善 DRE 患者的生活质量。该项目将利用磁共振- 引导低强度聚焦超声（MRg-FUS）可局部、可逆地打开血脑屏障 （BBB）以有针对性的方式而不产生热损伤。 BBB 的瞬时打开允许定时 将一种 BBB 不可渗透的神经毒素输送到脑实质，以产生局灶性、 目标神经元的轴突保留损伤。神经毒素喹啉酸 (QA) 在以下情况下具有良好的耐受性： 以高剂量全身给药，对完整 BBB 的渗透性很小或没有，相对而言 不受脑实质中谷氨酸摄取系统的影响，并且能够产生轴突 保留病变。我们在此提出系统性 QA 与 MRgFUS 相结合的第一个证据 产生局灶性神经元损伤，同时保留大脑精确目标区域的轴突。而且，这 方法提供了治疗那些很难（如果不是不可能的话）的目标的机会 目前可用的手术技术。最后，可以在实现这些结果的同时限制 附带损伤、手术副作用和长期神经功能缺损的风险。目前的项目将 使用边缘癫痫模型开发并测试这种限制癫痫发作的新方法。指导性的 假设是，可以通过精确的、有针对性的方式实现功能失调的大脑电路的有针对性的断开。 适形且非侵入性的方式，并且该策略可以用来控制癫痫发作和 改善神经系统结果。与目前的手术方式相比，这种方法具有明显的优势，因为 它将限制组织损伤的程度，允许治疗原本无法到达的区域，减少 围手术期并发症，减轻长期功能缺陷，并以非侵入性方式完成所有这一切 方式。值得注意的是，这种策略可能被证明可用于治疗多种神经系统疾病，其中 连接性的干扰发挥了作用。

Project Summary: Drug resistant epilepsy (DRE) remains a difficult biomedical challenge, affecting approximately one-third of newly-treated cases of epilepsy. Individuals impacted by DRE endure a poor quality of life, and can face life-threatening complications. Surgical removal of epileptogenic tissue can dramatically reduce seizures and improve quality of life. However, epilepsy surgery can be highly invasive, may produce damage that is not restricted to the target tissue, and is not feasible in certain critical areas of the brain. Also, surgical damage that is not conformal to its target and affects neighboring, eloquent tissue can produce long- term functional deficits. Finally, incomplete resection or ablation of target tissue can result in poor seizure management. The purpose of this proposal is to develop and test a non-invasive, targeted, conformal surgical strategy that will optimize seizure control, expand the types of epilepsies amenable to surgical intervention, and, ultimately, improve the quality of life of patients with DRE. This project will utilize Magnetic Resonance- guided, low-intensity Focused Ultrasound (MRg-FUS) to focally and reversibly open the blood brain barrier (BBB) in a targeted manner without producing a thermal lesion. Transient opening of the BBB allows timed delivery of an otherwise BBB-impermeable neurotoxin to the brain parenchyma in order to produce a focal, axon-sparing lesion of targeted neurons. The neurotoxin Quinolinic Acid (QA) is well tolerated when administered systemically at high dosages, exhibits little or no permeability through the intact BBB, is relatively unaffected by glutamatergic uptake systems in the brain parenchyma, and is capable of producing axon- sparing lesions. We present here the first evidence that systemically-administered QA combined with MRgFUS produces focal neuronal damage, while sparing axons in precisely targeted regions of the brain. Moreover, this approach affords the opportunity to treat targets that would be difficult, if not impossible, to treat using currently-available surgical techniques. Finally, these outcomes can be achieved while simultaneously limiting the risks of collateral damage, surgical side effects, and long-term neurological deficits. The current project will develop and test this novel approach for limiting seizures using a model of limbic epilepsy. The guiding hypothesis is that targeted disconnection of dysfunctional brain circuitry can be achieved in a precise, conformal, and non-invasive manner, and that this strategy can be implemented to control seizures and improve neurological outcomes. This approach provides distinct advantages over current surgical modalities as it will restrict the extent of tissue damage, allow treatment of regions that are otherwise inaccessible, reduce peri-surgical complications, mitigate against long-term functional deficits, and do all of this in a non-invasive manner. Notably, this strategy could prove useful for treating a variety of neurological disorders in which disturbances in connectivity play a role.