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

精确、非侵入性、保留轴突的手术治疗耐药性癫痫

• 批准号: 10357887
• 负责人: KEVIN Scott LEE
• 金额: $ 41.19万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10357887
• 关键词: Ablation; Affect; Animals; Antiepileptic Agents; Area; Axon; Blood - brain barrier anatomy; Blood coagulation; Brain; Brain region; Cells; Chronic; Communities; Corpus Callosum; Cortical Dysplasia; Data; Economics; Edema; Environment; Epilepsy; Excision; Exhibits; Face; Fiber; Focused Ultrasound; Focused Ultrasound Therapy; Glutamates; Goals; Hemorrhage; Individual; Infection; Injections; Intervention; Intractable Epilepsy; Lesion; Life; Long-Term Effects; Magnetic Resonance; Medical; Modality; Modeling; Nervous System Physiology; Neurologic Deficit; Neurological outcome; Neurological status; Neurons; Neurotoxins; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Permeability; Persons; Pharmacology; Play; Procedures; Quality of life; Quinolinic Acid; Recurrence; Risk; Rodent Model; Role; Seizures; Stroke; Structure; Surgical complication; System; Techniques; Temporal Lobe; Testing; Therapeutic; Tissues; World Health Organization; acronyms; brain circuitry; brain dysfunction; brain parenchyma; dosage; functional outcomes; gray matter; improved; minimally invasive; nervous system disorder; neurosurgery; neurotoxic; novel; novel strategies; preservation; side effect; uptake; white matter

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.

项目摘要： 耐药性癫痫（DRE）仍然是一个困难的生物医学挑战，影响 大约有三分之一的癫痫病病例。受到德雷影响的个人忍受着质量差 生活，可能面临威胁生命的并发症。癫痫组织的手术去除可以急剧 减少癫痫发作并改善生活质量。但是，癫痫手术可能具有高度侵入性，可能会产生 不限于目标组织的损害，并且在大脑的某些关键区域不可行。还， 手术损伤与其目标不符合并影响相邻的组织，雄辩的组织会产生长期的 术语功能缺陷。最后，靶组织的切除术或消融可能导致癫痫发作差 管理。该建议的目的是开发和测试无创，有针对性的保形手术 将优化癫痫发作，扩展可接受外科干预的癫痫类型的策略， 最终，提高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）以局部和可逆地打开血脑屏障 （BBB）以靶向方式而没有产生热病变。 BBB的瞬态开放允许定时 将原本不受BBB的神经毒素传递到脑实质中，以产生局灶性， 靶向神经元的轴突比较病变。当神经毒素喹啉酸（QA）耐受性良好 以高剂量为系统地给药，通过完整的BBB表现出很少或没有渗透性 不受脑实质中谷氨酸能吸收系统的影响，并且能够产生轴突 保留病变。我们在这里提出了第一个证据表明，全身管理的质量检查与mrgfus相结合 产生局灶性神经元损伤，同时在精确靶向大脑区域中保留轴突。而且，这 方法提供了治疗目标的机会 当前可用的手术技术。最后，可以同时限制这些结果 附带损害，手术副作用和长期神经系统缺陷的风险。当前项目将 开发和测试这种新型方法，使用边缘癫痫模型限制癫痫发作。引导 假设是，可以精确地实现靶向断开功能失调的脑回路连接 共形和非侵入性的方式，可以实施该策略以控制癫痫发作和 改善神经系统结果。这种方法比当前的手术方式具有不同的优势 它将限制组织损伤的程度，允许对原本无法访问的区域进行处理，减少 手术性并发症痛，减轻长期功能缺陷，并在非侵入性中做所有这些 方式。值得注意的是，该策略可能对治疗各种神经系统疾病有用 连通性的干扰起着作用。

项目成果

Targeted Neuronal Injury for the Non-Invasive Disconnection of Brain Circuitry.

用于非侵入性断开脑回路的靶向神经元损伤。

• DOI: 10.3791/61271
• 发表时间: 2020
• 期刊: Journal of visualized experiments : JoVE
• 作者: Wang,Wilson;Zhang,Yanrong;Anzivino,MatthewJ;Bertram,EdwardH;Woznak,James;Klibanov,Alexander;Dumont,Erik;Wintermark,Max;Lee,KevinS
• 通讯作者: Lee,KevinS

Defining the optimal age for focal lesioning in a rat model of transcranial HIFU.

确定经颅 HIFU 大鼠模型中局灶性病变的最佳年龄。

• DOI: 10.1016/j.ultrasmedbio.2014.09.029
• 发表时间: 2015
• 期刊: Ultrasound in medicine & biology
• 影响因子: 2.9
• 作者: Zhang,Yanrong;Aubry,Jean-François;Zhang,Junfeng;Wang,Yi;Roy,Jack;Mata,JaimeF;Miller,Wilson;Dumont,Erik;Xie,Mingxing;Lee,Kevin;Zuo,Zhiyi;Wintermark,Max
• 通讯作者: Wintermark,Max

Corrigendum to 'Molecular Identity Changes of Tumor-Associated Macrophages and Microglia After Magnetic Resonance Imaging-Guided Focused Ultrasound-Induced Blood-Brain Barrier Opening in a Mouse Glioblastoma Model' [Ultrasound in Med & Biol. 49 (2023) 108

“小鼠胶质母细胞瘤模型中磁共振成像引导聚焦超声诱导血脑屏障开放后肿瘤相关巨噬细胞和小胶质细胞分子身份变化的勘误”[医学中的超声]

• DOI: 10.1016/j.ultrasmedbio.2023.12.016
• 发表时间: 2024
• 期刊: Ultrasound in medicine & biology
• 影响因子: 2.9
• 作者: Zhang,Yanrong;Wang,Jing;Ghobadi,SaraNatasha;Zhou,Haiyan;Huang,Ai;Gerosa,Marco;Hou,Qingyi;Keunen,Olivier;Golebiewska,Anna;Habte,FrezghiG;Grant,GeraldA;Paulmurugan,Ramasamy;Lee,KevinS;Wintermark,Max
• 通讯作者: Wintermark,Max

Effects of Non-invasive, Targeted, Neuronal Lesions on Seizures in a Mouse Model of Temporal Lobe Epilepsy.

• DOI: 10.1016/j.ultrasmedbio.2020.01.008
• 发表时间: 2020-05
• 期刊: Ultrasound in medicine & biology
• 影响因子: 2.9
• 作者: Zhang Y;Zhou H;Qu H;Liao C;Jiang H;Huang S;Ghobadi SN;Telichko A;Li N;Habte FG;Doyle T;Woznak JP;Bertram EH;Lee KS;Wintermark M
• 通讯作者: Wintermark M

Testing Different Combinations of Acoustic Pressure and Doses of Quinolinic Acid for Induction of Focal Neuron Loss in Mice Using Transcranial Low-Intensity Focused Ultrasound.

使用经颅低强度聚焦超声测试声压和喹啉酸剂量的不同组合对小鼠局灶神经元损失的诱导作用。

• DOI: 10.1016/j.ultrasmedbio.2018.08.023
• 发表时间: 2019
• 期刊: Ultrasound in medicine & biology
• 影响因子: 2.9
• 作者: Zhang,Yanrong;Liao,Chengde;Qu,Haibo;Huang,Siqin;Jiang,Hong;Zhou,Haiyan;Abrams,Emily;Habte,FrezghiG;Yuan,Li;Bertram,EdwardH;Lee,KevinS;Pauly,KimButts;Buckmaster,PaulS;Wintermark,Max
• 通讯作者: Wintermark,Max