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

基本信息

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
项目类别：
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

项目摘要

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个很大程度上棘手的医学问题，大多数病例对抗惊厥药物的反应较差，并且由于神经学缺陷的可能性而受到限制。由于大量信息处理是在皮层中垂直组织的，而癫痫发作的传播主要是通过横向连接发生的，因此一系列切口可以防止传播或开始癫痫发作，但在很大程度上保留了功能。这些切口一定不能切断脑表面上的血管，并且尚不清楚哪些皮质层最好切割，以实现最佳的癫痫发作控制和最小的神经系统影响。紧密的飞秒激光脉冲提供了一种独特的工具，可以使微尺尺寸切割在大部分的组织内，并具有最小的附带损害。我们假设使用这些切割来横断靶向皮质层中的神经连接将阻止局部启动癫痫发作的启动或传播。因为这些切割仅针对特定皮层中的水平连接，并且保留了皮质的大多数神经连接性，因此将最少神经缺陷。该提案的主要目标是确定要切割哪个皮质层，以及哪些几何模式可以最大程度地干扰癫痫发作和传播，同时最小化了正常功能。在AIM 1中，我们测试了飞秒激光切割的急性疗效，以防止癫痫发作和传播。癫痫发作是通过将4-氨基吡啶显微注射到皮层中的大鼠中模拟的。局部现场电位记录和两光钙敏感染料成像用于监测神经活动和癫痫发作。飞秒激光消融用于用地下切割包围或细分癫痫发起位点。首先，我们确定必须透射哪些皮层层，以防止癫痫发作在包围区域外传播。目的是确定要切割的癫痫发作的最小层数。基于最新数据，这表明临床癫痫发作是由微蛋白的合并引起的，我们接下来研究了在癫痫发作部位切开的网格模式是否可以通过分离微区域来防止癫痫发作。在AIM 2中，我们通过记录晶须刺激后体感皮质中诱发信号的变化，探索AIM 1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基于激光的新型外科手术方法，用于治疗局灶性新皮层癫痫。此外，这项工作将提供有关皮质层特异性启动和癫痫发作的有价值的体内数据。如果此处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了成功的实施，那么使用最近开发的激光技术是可行的，并且可以在Sulci底部以外的所有底部生产出层特异性的切割，从而为新的外科手术治疗开放了新的外科手术治疗。