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非常棘手的医学问题，大多数病例对抗惊厥药物反应不佳，并且由于可能出现神经功能缺损，目前的手术治疗选择有限。由于许多信息处理是在皮质中垂直组织的，而癫痫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引发癫痫发作，但很大程度上保留了功能。这些切口不得切割大脑表面的血管，目前尚不清楚哪些皮质层最好被切割以实现最佳的癫痫控制和最小的神经系统影响。紧密聚焦的飞秒激光脉冲提供了一种独特的工具，可以在大块组织内进行几毫米的微米级切割，同时将附带损伤降至最低。我们假设，使用这些切口横断目标皮质层中的神经连接将阻止局灶性癫痫发作的发生或传播。因为这些切割仅针对特定皮质层中的水平连接，并且保留了皮质的大部分神经连接，所以将有最小的神经功能缺损。该提案的主要目标是确定应切割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发生和传播，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功效。通过将 4-氨基吡啶显微注射到皮质中来模拟大鼠癫痫发作。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。飞秒激光消融用于通过表面下切割来包围或细分癫痫发作起始部位。首先，我们确定必须横断哪些皮质层，以防止癫痫发作传播到包围区域之外。目标是确定控制癫痫发作所需切割的最小层数。最近的数据表明临床癫痫发作是由微癫痫发作合并引起的，我们接下来研究在癫痫发作起始部位切开的网格图案是否可以通过分离微域来防止癫痫发作。在目标 2 中，我们通过记录胡须刺激后体感皮层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手术方法，用于治疗局灶性新皮质癫痫。此外，这项工作将为癫痫发作的皮质层特异性启动和传播提供有价值的体内数据。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，并且将能够在除脑沟底部之外的所有区域中产生特定层的切割。，为癫痫新的手术治疗打开了大门。