Femtosecond laser-produced sub-surface cuts to halt focal epileptic seizures

飞秒激光产生的表面下切割可阻止局灶性癫痫发作

• 批准号: 8551771
• 负责人: CHRIS B SCHAFFER
• 金额: $ 23.82万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8551771
• 关键词: 4-Aminopyridine; Ablation; Acute; Adverse effects; Affect; Animal Model; Basic Science; Biological Preservation; Biomedical Engineering; Blood Circulation; Blood Vessels; Brain; Calcium; Cells; Chemicals; Chronic; Clinical; Collaborations; Containment; Data; Dyes; Effectiveness; Epilepsy; Excision; Fluorescence; Future; Goals; Grant; Human; Image; Injection of therapeutic agent; Interruption; Laboratory Research; Lasers; Lateral; Left; Location; Medical; Methods; Microinjections; Modeling; Molecular; Monitor; Morbidity - disease rate; Neocortex; Neurologic; Neurons; Neurosciences; Neurosurgeon; Operative Surgical Procedures; Optics; Partial Epilepsies; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacology; Physiologic pulse; Process; Rattus; Research; Research Personnel; Rodent; Seizures; Series; Side; Signal Transduction; Site; Somatosensory Cortex; Stimulus; Surface; Surgical incisions; Techniques; Technology; Testing; Tissues; Universities; Vibrissae; Width; Work; base; brain tissue; in vivo; information processing; medical schools; millimeter; neocortical; novel; prevent; public health relevance; relating to nervous system; research study; response; somatosensory; therapy development; tool; two-photon

DESCRIPTION (provided by applicant): Focal neocortical epilepsy is a largely intractable medical problem, with most cases responding poorly to anti-convulsive medications and current surgical treatment options limited because of the likelihood of neurological deficits. Because much information processing is vertically organized in cortex, while seizure propagation occurs primarily through lateral connections, a series of incisions could prevent the spread or initiation of seizures but largely preserve function. These incisions must not cut the blood vessels on the brain surface and it remains unclear which cortical layers are best cut to achieve optimal seizure control and minimal neurological impact. Tightly-focused femtosecond laser pulses provide a unique tool to make micrometer-scale cuts several millimeters within the bulk of a tissue with minimal collateral damage. We hypothesize that using these cuts to transect the neural connections in targeted cortical layers will block the initiation or propagation of focally initiatd epileptic seizures. Because these cuts target only horizontal connections in a specific cortical layer and the majority of the neural connectivity of the cortex is preserved, there will be minimal neurological deficit. A primary goal of this proposal is to determine which cortical layer(s) shoul be cut and in what geometric pattern to maximally interfere with seizure initiation and propagation while minimally affecting normal function. In Aim 1, we test the acute efficacy of femtosecond laser cuts to specific cortical layers in preventing epilepsy initiation and propagation. Epileptic seizures are modeled in rats by microinjection of 4-aminopyridine into cortex. Local field potential recordings and two-photon calcium sensitive dye imaging are used to monitor neural activity and seizure propagation. Femtosecond laser ablation is used to encircle or subdivide the seizure initiation site with subsurface cuts. First, we determine which cortical layers must be transected to prevent seizures from propagating outside of the encircled region. The goal is to determine the minimum number of layers to cut for seizure containment. Building on recent data that suggests that clinical seizures result from the coalescence of microseizures, we next investigate whether a grid pattern incised at the seizure initiation site can prevent seizure initiation by separating microdomains. In Aim 2, we explore potential side effects of the most promising laser cuts from Aim 1 by recording changes in evoked signals in somatosensory cortex after whisker stimulation. These experiments will test, in animal models, a new laser-based surgical method for the treatment of focal neocortical epilepsy. In addition, this work will provide valuable, in vivo data on cortical layer- specific initiation and propagatio of seizures. If the acute animal model experiments proposed here as well as future studies that evaluate the longer-term effectiveness prove successful then human implementation is feasible using recently-developed laser technology and would enable layer-specific cuts to be produced in all but the bottom of sulci, opening the door to new surgical treatments for epilepsy.

描述（由申请人提供）：局灶性新皮质癫痫是一种很难治疗的医学问题，大多数病例对抗惊厥药物反应不佳，由于可能存在神经功能缺损，目前的手术治疗选择有限。由于许多信息处理是在皮层中垂直组织的，而癫痫发作传播主要通过横向连接发生，因此一系列切口可以阻止传播或启动 但基本上保留了功能。这些切口不得切割大脑表面的血管，目前还不清楚哪些皮层最好切割，以实现最佳的癫痫控制和最小的神经影响。紧密聚焦的飞秒激光脉冲提供了一种独特的工具，可以在大部分组织内进行几毫米的微米级切割，同时附带损伤最小。我们假设，使用这些切口横切目标皮质层的神经连接将阻断局灶性癫痫发作的开始或传播。因为这些切割仅针对特定皮质层中的水平连接，并且皮质的大部分神经连接被保留，所以将存在最小的损伤。 神经缺陷该提议的主要目标是确定应该切割哪个（哪些）皮质层以及以何种几何图案来最大程度地干扰癫痫发作的开始和传播，同时最小程度地影响正常功能。在目标1中，我们测试了飞秒激光切割特定皮质层在预防癫痫发作和传播方面的急性疗效。通过向皮质中微量注射4-氨基吡啶在大鼠中建立癫痫发作模型。局部场电位记录和双光子钙敏感染料成像用于监测神经活动和癫痫发作传播。飞秒激光消融用于环绕或细分癫痫发作起始部位，并进行表面下切割。首先，我们确定哪些皮质层必须被横切，以防止癫痫发作蔓延到周围区域之外。目标是确定为遏制癫痫发作而切割的最少层数。最近的数据表明，临床癫痫发作的结果，从合并的微癫痫发作，我们接下来调查是否在癫痫发作的起始位点切割的网格图案可以防止癫痫发作的起始分离微域。在目标2中，我们通过记录胡须刺激后体感皮层中诱发信号的变化来探索目标1中最有前途的激光切割的潜在副作用。这些实验将在动物模型中测试一种新的基于激光的治疗局灶性新皮质癫痫的手术方法。此外，这项工作将提供有价值的，在体内数据皮质层特异性启动和传播的癫痫发作。如果这里提出的急性动物模型实验以及评估长期有效性的未来研究证明是成功的，那么使用最近开发的激光技术进行人类实施是可行的，并且可以在除脑沟底部之外的所有部位进行特定层的切割，为癫痫的新手术治疗打开大门。