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

项目总结： 耐药癫痫(DRE)仍然是一个困难的生物医学挑战，影响 在新治疗的癫痫病例中，约有三分之一。受DRE影响的个人承受着糟糕的质量 可能会面临危及生命的并发症。外科手术切除致痫组织可以极大地 减少癫痫发作，提高生活质量。然而，癫痫手术可以是高度侵入性的，可能会产生 损伤不仅限于目标组织，而且在大脑的某些关键区域是不可行的。另外， 与目标不适形并影响邻近雄辩组织的外科损伤可产生长时间的 终末期功能缺陷。最后，不完全切除或消融靶组织可导致癫痫发作不良。 管理层。这项建议的目的是开发和测试一种非侵入性的、有针对性的、适形的外科手术 战略将优化癫痫控制，扩大可接受手术干预的癫痫类型， 并最终提高DRE患者的生活质量。该项目将利用核磁共振- 引导低强度聚焦超声(MRG-FUS)定向可逆地打开血脑屏障 (Bbb)以有针对性的方式进行，而不会产生热损伤。BBB的瞬时打开允许定时 将一种不透血脑屏障的神经毒素输送到脑实质，以产生病灶， 靶向神经元的轴突保护损伤。神经毒素喹啉酸(QA)在以下情况下耐受性良好 以高剂量全身给药，对完整的血脑屏障几乎或没有渗透性，相对来说 不受脑实质中谷氨酸摄取系统的影响，并能够产生轴突- 避免损伤。我们在这里提出了系统管理的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。此外，这一点 方法提供了治疗目标的机会，这些目标即使不是不可能治疗，也很难使用 目前可用的外科技术。最后，可以在限制的同时实现这些结果 附带损害、手术副作用和长期神经缺陷的风险。当前项目将 利用边缘癫痫模型开发和测试这种限制癫痫发作的新方法。引路人 假设有针对性地切断功能失调的大脑回路可以精确地实现， 适形和非侵入性方式，这一战略可用于控制癫痫发作和 改善神经学结果。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，允许治疗原本无法进入的区域，减少 围手术期并发症，减轻长期功能障碍，并在非侵入性 举止。值得注意的是，这一策略可能被证明对治疗各种神经疾病很有用，在这些疾病中 连通性方面的干扰起到了一定作用。

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.