作者要感谢佩德罗A.巴尔德斯埃尔南德斯，弗朗索瓦Tadel和劳埃德·史密斯提出宝贵的意见和富有成果的讨论。我们也感谢拉斐尔托雷斯的校对。

伦理声明：所有实验以下的机构动物护理和使用委员会（IACUC）在佛罗里达国际大学（IACUC 13-004）确定的政策执行。 1.脑电图记录<ol><li>脑电图迷你帽的制备<ol><li>沉浸脑电图迷你帽至少12小时在蒸馏水中0.2％的氯化钠的电极尖端。在蒸馏水轻轻冲洗脑电图迷你帽。干燥的盖和在空气中的电极。 </li><li>混合脑电图电极糊在2体积比例的0.9％NaCl溶液：1.添加一滴亚甲蓝的，这将有助于可视化的电极浆料内的电极和在皮肤上。以混合浆料中的注射器。确保有没有气泡在注射器。注入凝胶到每个32电极，填充它们，而不会引入任何气泡。建议从底部而不是顶部注入。这提供了更好的ACCESS到每个电极，并降低了凝胶的蔓延的可能性。 </li><li>打开EEG和生理记录系统，并在计算机上使用打开相应的记录软件。 </li></ol></li><li>动物准备及麻醉 注：慢性癫痫是使用协议FCD 8 Wistar大鼠产生。 （ - 400克8周龄，300）脑电图记录是在成年大鼠进行。 <ol><li>记录大鼠的体重在实验片。使用该信息来计算剂量的镇静剂（dexdomitor 0.25毫克/千克）。在用5％异氟醚和100％的氧气（1升/分，在14.7 psi）的大鼠诱导麻醉。 </li><li>修剪后大鼠的头，减少异氟烷至2％，脑电图迷你盖的整个设置过程中保持它。检查大鼠反射消失（趾捏）。通过固定用耳棒耳道放置在加热垫上在立体定位仪的鼠。确保麻醉鼻锥是安全的。 </li><li>美联社来往润滑剂眼药膏每只眼睛。 </li><li>刮胡子使用剃刀鼠头部和耳朵额外的头发。避免剃须过程中的任何出血。 注：在皮肤上留下会产生噪音，在脑电图记录的任何毛发。擦大鼠皮肤用90％的异丙醇，刺激血管和皮肤脱脂。 </li><li>将头皮上的盐水擦拭，并完全覆盖它来保持良好的皮肤电导直到脑电图迷你上限是准备放置。 </li><li>连接温度，呼吸，和三个导联心电图探头。注意，该温度是由直肠探头测量。连续监视的大鼠的生理过程中记录的程序。确保正常温度为37℃，呼吸范围是30 - 每分钟60次呼吸和心脏速率是约350 - 每分钟450次。 </li></ol></li><li>录音程序<ol><li>取出盐水擦拭对大鼠的头皮，然后将准备好的微型脑电图-CAP在它的皮肤。修复迷你帽用橡皮筋。放置一个橡胶带在头皮上的前侧，通常是在眼睛的前面，而另一个带在耳朵和颈部之间的头皮的背面。使用颈下一个塑料保护，以促进正常的呼吸。 </li><li>放一层高电导电极糊的同时在地面和参考电极。把他们放在各自的耳朵。 注：参考电极可可能放置在其它位置。 </li><li>连接脑电图迷你帽放大器和观察工作台电极阻抗的预览。检查所有电极的性能。对于高品质录音，保证阻抗值是5的范围内 - 30千欧。如果有任何嘈杂电极，提供通过移动他们的脚手架内朝向头皮或轻轻地从电极的顶部注入更多的凝胶与头皮接触更好。 </li><li>辖dexdomitor（0.25毫克/千克）intraperitoneally并立即降低异氟烷率为0％。如果呼吸率不在30 - 每分钟为60次呼吸，轻轻地开始增加异氟醚率。不超过1％，异氟醚的价值。仔细监测这一步骤，因为异氟醚和dexdomitor的混合物可能会促使动物病情危重。 注：在局灶性癫痫的临床前模型，异氟醚影响简易爆炸装置，而dexdomitor没有。异氟醚下有科目致痫较弱财产， 也就是说，相对较少的简易爆炸装置可以相对于其他条件7,14进行检测。该dexdomitor剂量是有效约2小时。因此，为了节省时间，其效果，进行制备在异氟烷。 </li><li>进行脑电图记录。在记录之后，通过脑电图迷你帽之前插入它们内部的彩色笔被去除标记在皮肤上的顶部的脑电图迷你帽的三个突出的圆的位置上。用它们作为MRI共地标-registration。就拿老鼠头的标志性建筑的照片。将大鼠背部的笼子里面和监控，直到从dexdomitor的效果完全恢复。 注意：在这个实验中，红色（对手颜色为绿色）被用来从电极位置（绿色）区分。然而，建议使用其他颜色（紫色/绿色）如小出血斑的皮肤中观察到。 </li></ol></li></ol><img alt="图1" src="/files/ftp_upload/52700/52700fig1.jpg" /> 图1.脑电图迷你帽放置在一个特定的大鼠的图片。 <a href="https://www.jove.com/files/ftp_upload/52700/52700fig1highres.jpg" target="_blank">请点击此处查看该图的放大版本。</a> 2.脑源成像<ol><li> IED分类 注：使用MATLAB中自主开发的代码基础上，该装置检测和分级进行的先前的研究[15]。该软件将可根据用户要求。 <ol><li>通过目视检查脑电图示踪剂丢弃嘈杂的渠道。除去使用自动方法用于周期性波形减法，它是基于一个模板和相关分析的EKG工件。 注意：通常情况下，谁记录脑电图实验者共享书面试验片为基于所述阻抗值中的观察到的不良的信道信息。软件删除EKG文物也将可根据用户要求。 <img alt="图2" src="/files/ftp_upload/52700/52700fig2.jpg" /> 图2.脑电图显示跟踪不同类型的智能电子设备的一个例子。红色框表示一种类型的简易爆炸装置。 <a href="https://www.jove.com/files/ftp_upload/52700/52700fig2highres.jpg" target="_blank">请点击此处查看该图的放大版本。</a> </li><li>应用的带通滤波器中的3截止频率 - 150赫兹和切口过滤以除去线频率（60赫兹一般，在有些国家50 Hz）分量脱机。 </li><li>检测两种类型的简易爆炸装置（尖峰和尖波）。尖峰和尖波构成的20个大型电器事件 - 70毫秒和70 - 200分别在毫秒时间。因此，施加各自的带通滤波器（15截止频率- 50赫兹的尖峰和5 - 15赫兹为尖锐波）后，所述智能电子设备是基于振幅阈值15检测。 注：该阈值被自动设置为4σ如在先前的研究中对多组活动15建议。这里，σ是带通滤波信号的估计的标准偏差，σ=中间值{|滤波后的信号| / 0.6745}。 </li><li>子分类尖峰和尖波成不同的集群。不同的尖峰和尖波的显着特点是利用小波变换15提取。它们分分类使用k均值为多个集群，和最优簇数k用剪影来确定。 </li><li>同一群集内平均的子分类的信号。对于各IED子类型的平均EEG信号将被用于脑源的分析。 </li></ol></li><li>卷导体模型 注：以下章节中，开源软件，头脑风暴12，将与MRI地图集Wistar大鼠9中。然而，个别大鼠的MRI还可以用于如果可用来产生体积导体模型。该地图集MRI 9可以在下载<a href="http://www.idac.tohoku.ac.jp/bir/en/db/rb/101028.html">http://www.idac.tohoku.ac.jp/bir/en/</a> 。该网站提供的地图册作为NIFTI格式“的Wistar大鼠MRI地图集”部分下，它可以是注册后访问。所需的前处理的软件也可以发现在这个网站。 <ol><li>输入MRI和脑表面到软件12。 <img alt="视觉1" srC =“/文件/ ftp_upload / 52700 / 52700vis1.jpg”/&gt; <a href="https://www.jove.com/files/ftp_upload/52700/52700vis1highres.jpg" target="_blank">请点击此处查看该图的放大版本。</a> </li><li>产生头表面采用默认设置。 <img alt="视觉2" src="/files/ftp_upload/52700/52700vis2.jpg" /> <a href="https://www.jove.com/files/ftp_upload/52700/52700vis2highres.jpg" target="_blank">请点击此处查看该图的放大版本。</a> </li><li>生成基于MRI铅场计算12头皮和内/外表面的头骨。 注：顶点的分辨率影响估计源的精确度，但大量的顶点导致高计算复杂度。每一层的顶点数量，建议642是可接受的准确性与公平的计算复杂度。头骨的厚度可从MRI检查，并且在MRI图谱的情况下，它是约1μm米在软件中插入上述值，相应的三角脸顶点网格后，每个表面将被创建。 <img alt="视觉3" src="/files/ftp_upload/52700/52700vis3.jpg" /> <a href="https://www.jove.com/files/ftp_upload/52700/52700vis3highres.jpg" target="_blank">请点击此处查看该图的放大版本。</a> </li><li>检查每个表面的取向和位置使用可视化选项对于MRI检查。进行相应的修改，如果任何表面不共配准12。 <img alt="视觉4" height="351" src="/files/ftp_upload/52700/52700vis4.jpg" width="321" /> <a href="https://www.jove.com/files/ftp_upload/52700/52700vis4highres.jpg" target="_blank">请点击此处查看该图的放大版本。</a> </li><li>在使用1.3.5收购老鼠头像。共登记的3界标（R1，R2和R3）在MRI的位置。使用的地标网格点作为参考来克enerate的电极位置，电极被固定在支架上（ 图3B）。 <img alt="图3" src="/files/ftp_upload/52700/52700fig3.jpg" /> 图3.（A）老鼠头像用来获取电极位置和（b）脑电图迷你帽图的坐标系。红点在（A）表示在1.3.5中提到的地标。对应于红色的数字中的（B）。另外，在绿色标记（A）中描述了32电极位置，并且它们对应于蓝色的数字中的（B）。 <a href="https://www.jove.com/files/ftp_upload/52700/52700fig3highres.jpg" target="_blank">请点击此处查看该图的放大版本。</a> </li><li>基于所述3界标为N×3电极位置矩阵。这里，N是信道数（N = 32）和列表示相应的x，y和z坐标值。 注：脑电图迷你帽是刚性支架。因此，一旦3参考网格（R1，R2和R3）都得到，电极的位置被自动设定。用户将仅需要重新定义上的方式使微型帽适当地投射在头皮的Z值。如在图3B蓝色数字描绘了N点网格，可以按顺序编号。该标准支架的脑电图迷你帽可购（ 表材料 ）。该软件为共同注册也可到社区。 </li><li>输入所产生的信道的文件。 <img alt="视觉5" src="/files/ftp_upload/52700/52700vis5.jpg" /> <a href="https://www.jove.com/files/ftp_upload/52700/52700vis5highres.jpg" target="_blank">请点击此处查看该图的放大版本。</a> </li><li>显示并确认所有电极的位置。修改任何错位电极12。最终的坐标电系统德位置应与用于上述表面的坐标系一致。 注：创建的表面可以通过使用可视化选项，进行目视检查上的MRI然后，选定的表面将被显示为在磁共振成像黄线“MRI检查登记检查MRI /表面登记”。此外，3地标和32的电极位置可以通过选择工具箱的选择，显示在MRI“查看传感器磁共振查看器。”的位置可以通过基于大鼠的眼睛和耳朵的位置进行比较的分布（进行目视检查图4）。 <img alt="图4" src="/files/ftp_upload/52700/52700fig4.jpg" /> 图4.（A）的磁共振图谱与共同注册脑表面（黄线），（B）和对准32的电极和第3界标（红点）创建的卷导体模型，和（C）的核磁共振图谱与共同配准REF<html> erence电网R1。 <a href="https://www.jove.com/files/ftp_upload/52700/52700fig4highres.jpg" target="_blank">请点击此处查看该图的放大版本。</a> </li></ol></li><li>脑源成像<ol><li>计算铅场矩阵13。输入满足皮肤，颅骨和脑的比率为1的电导率值：1/80：1.获得基于体积导体模型和2.2产生的电极的位置的导线场矩阵。 注：该工具箱12提供的接口与其他软件计算BEM 10。因此，只有电导率值是必需作为输入。 <img alt="6视觉" src="/files/ftp_upload/52700/52700vis6.jpg" /> <a href="https://www.jove.com/files/ftp_upload/52700/52700vis6highres.jpg" target="_blank">请点击此处查看该图的放大版本。</a> </li><li>输入每个IED子类型存储在2.1.4平均EEG信号。 “SRC =”/文件/ ftp_upload / 52700 / 52700vis7.jpg“/&gt; <a href="https://www.jove.com/files/ftp_upload/52700/52700vis7highres.jpg" target="_blank">请点击此处查看该图的放大版本。</a> </li><li>获取基于所计算的铅场矩阵和输入EEG信号sLORETA溶液13。通过选择源估计方法选项，逆溶液可以得到12。 <img alt="视觉8" src="/files/ftp_upload/52700/52700vis8.jpg" /> <a href="https://www.jove.com/files/ftp_upload/52700/52700vis8highres.jpg" target="_blank">请点击此处查看该图的放大版本。</a> </li><li>绘制估计来源。 </li></ol></li></ol>

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M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=FieldTrip:+Open+Source+Software+for+Advanced+Analysis+of+MEG,+EEG,+and+Invasive+Electrophysiological+Data.">FieldTrip: Open Source Software for Advanced Analysis of MEG, EEG, and Invasive Electrophysiological Data.</a> Computational Intelligence and Neuroscience. 2011, 1-9 (2011).</li><li>Koessler, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Source+localization+of+ictal+epileptic+activity+investigated+by+high+resolution+EEG+and+validated+by+SEEG.">Source localization of ictal epileptic activity investigated by high resolution EEG and validated by SEEG.</a> NeuroImage. 51 (2), 642-653 (2010).</li><li>Manganotti, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Scalp+topography+and+source+analysis+of+interictal+spontaneous+spikes+and+evoked+spikes+by+digital+stimulation+in+benign+rolandic+epilepsy.">Scalp topography and source analysis of interictal spontaneous spikes and evoked spikes by digital stimulation in benign rolandic epilepsy.</a> Electroencephalography and Clinical Neurophysiology. 107 (1), 18-26 (1998).</li><li>Bae, J., Deshmukh, A., Song, Y., Brain Riera, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Source+Analysis+of+Interictal+Epileptiform+Discharges+Using+a+Rat+Model+of+Focal+Epilepsy.">Source Analysis of Interictal Epileptiform Discharges Using a Rat Model of Focal Epilepsy.</a> Organization for Human Brain Mapping. , (2014).</li><li>Birot, G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Head+model+and+electrical+source+imaging:+A+study+of+38+epileptic+patients.">Head model and electrical source imaging: A study of 38 epileptic patients.</a> NeuroImage: Clinical. 16 (5), 77-83 (2014).</li><li>Riera, J. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pitfalls+in+the+dipolar+model+for+the+neocortical+EEG+sources.">Pitfalls in the dipolar model for the neocortical EEG sources.</a> Journal of Neurophysiology. , (2012).</li><li>Hawrylycz, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+Allen+Brain+Atlas.">The Allen Brain Atlas.</a> Springer Handbook of Bio-Neuroinformatics. , 1111-1126 (2014).</li><li>Schweinhardt, P., Fransson, P., Olson, L., Spenger, C., Andersson, J. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+template+for+spatial+normalization+of+MR+images+of+the+rat+brain.">A template for spatial normalization of MR images of the rat brain.</a> Journal of Neuroscience Methods. 129 (2), 105-113 (2003).</li><li>Schwarz, A. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+stereotaxic+MRI+template+set+for+the+rat+brain+with+tissue+class+distribution+maps+and+co-registered+anatomical+atlas:+application+to+pharmacological+MRI.">A stereotaxic MRI template set for the rat brain with tissue class distribution maps and co-registered anatomical atlas: application to pharmacological MRI.</a> Neuroimage. 32 (2), 538-550 (2006).</li></ol>

没有利益冲突的声明。

一种新的方法，以非侵入性地记录多信道脑电图局灶性癫痫的特定临床前模型中进行说明。用于记录和分析程序的详情，与具体的实验提示，提供。有考虑取得成功结果的关键因素。首先，脑电图记录，获得高品质的信号是必不可少的。脑电图糊的适当粘度应该迷你帽制备过程中施加到每个电极，以及鼠的头部和耳朵发应在剃刮期间被完全除去。阻抗检查是为了确认脑电图记录质量的最重要的一步。其次，脑成像来源，产生量适当导体模式是至关重要的。每个表面应共登记。此外，所产生的电极的位置应具有对大鼠的头皮的实际电极的位置的最小距离误差。 尽管这个手稿源介绍采用头脑风暴12分析程序，他们可以使用其他软件开放16,17和商业产品18,19进行。此外，除了sLORETA 13，其他逆解决方案，如多偶极模型和波束形成器可用于4。 这种方法的一个限制是，行为分析，不能进行自脑电图记录镇静下进行。然而，相对于其它方法的脑电图记录大鼠5,6，这种方法是非侵入性的。 我们的初步结果支持为从脑电图记录IED标记，以确定在局灶性癫痫大鼠的刺激性区，以及评估其与癫痫发作起始11的基本机制关系的精确分类的重要性。此外，已经表明，脑电图源定位为这样的特定的IED表现出良好的对应关系与RESPective BOLD激活和去激活区20。 我们的研究将刺激使用临床前模型来评价生物医学工程师研制床工作台床的策略。例如，时下是手动的医院，这需要大量的人力精力进行IED提取。在这项研究中提出的方法自动完成。我们推测，当施加到患者FCD使用这种方法会产生类似的结果。我们正在准备的IRB协议的这个评价和对人的数据集的方法的其他方面。 此外，使用临床前模型将帮助我们理解在癫痫脑电图21源定位的能力和局限。脑源下属的癫痫准确的估计是治疗策略和手术规划至关重要。此外，具有大鼠脑电记录一个标准的平台将是有益的几种抗癫痫药物在临床前试验中的效力的评估。这是第一个研究中，癫痫的大鼠都记录非侵入镇静下，这将打开新的大门脑电图生物标志物用于癫痫的评价。然而，在该研究中提出的整个方法可延伸到其他的实验条件和脑部疾病。脑电图迷你帽，也可以使用在其他啮齿动物的类型。 在过去，在Wistar大鼠中一个前爪刺激范例已被用于评估记录的脑电图迷你盖2的数据的质量和再现性。此外，验证为脑源重建已执行从高分辨率颅骨脑电图同时录制与来自Wistar大鼠层局部场电位下一个晶须刺激范例22。这种方法已经开发Wistar大鼠，因为核磁共振图谱的存在对于这个特殊的鼠s火车。但是，它可以被应用到其它啮齿动物类型与图谱包括鼠标23，Sprague-Dawley大鼠24，以及Paxinos和Watson大鼠25的自己的标准格式。此外，我们所提出的方法的基本程序可在任何啮齿类动物临床前模型的量脑电​​图是一个重要的方式被使用。然而，这种方法的许多方面都特别为癫痫，特别是那些与脑电图预处理（IED检测和分类）。此外，研究人员必须知道在不同情况下使用镇静药物的正确。在我们的研究中使用异氟醚和dexdomitor已精心由于对简易爆炸装置的影响减少考虑。关于脑电图记录，在小鼠的情况下，相对小的头皮表面面积将大大减少信道数。

It has been shown that interictal epileptiform discharges (IEDs) observed from EEG constitute useful markers of epileptogenesis in patients with focal epilepsy3. The regions inside the brain from which these IEDs originate, named irritative zones, can in practice be localized based on EEG recordings4. Preclinical models are essential to find correlates between these irritative zones and the actual regions underlying seizure initiation. However, recording EEG from small animals is challenging because of the small surface area of the head compared to the human scalp. Although invasive methods for chronic recording in rats can be used5, 6, techniques are not available at this moment to acquire traditional EEG recordings on rodents under acute conditions without the need of anesthesia.
To solve this problem, we apply a patented EEG mini-cap2, which allows us to record 32-channel EEG data from rodents noninvasively. In this study, we also provide evidence about the need of an analgesic to preserve IED frequency. Therefore, although fixation of EEG mini-cap was performed under isoflurane, EEG recordings were obtained with rats only under sedation (dexdomitor)7. The method proposed in this study can be used in any preclinical rat model of focal epilepsy. To illustrate the capabilities of this methodology, we apply it to understand the correlates between irritative and seizure-onset zones in focal cortical dysplasia (FCD). To that end, we use a &#8220;double-hit&#8221; model of FCD8 in Wistar rats.
To perform brain source analysis, it is required to: a) accurately extract IEDs from EEG raw data and b) obtain a volume conductor model for the individual animal head. To generate a practical volume conductor model, we use an in vivo rat MRI atlas, comprising average images of intensity/shape and obtained via non-linear registration of T2 images of 31 Wistar rats9. The forward model for the generated volume conductor was computed by boundary element method (BEM)10. As in the case of humans, two typical patterns of IEDs (sharp-waves and spikes) were detected and sub-classified into different clusters through an intelligent feature extraction, feature selection, and classification process11. These sub-classified signals are used to estimate the brain source localizations associated with different types of irritative zones. We present the source analysis steps using a well-known public software called Brainstorm12. The EEG source localizations for each IED sub-type and the seizure onset time frames were performed using standardized low-resolution brain electromagnetic tomography (sLORETA)13, which is available in Brainstorm.

<table border="0" cellpadding="0" cellspacing="0">
	<tbody>
		<tr>
			<td>Data Qcquisition Computer</td>
			<td>Hewlett-Packard</td>
			<td>Z210 Workstation</td>
			<td></td>
		</tr>
		<tr>
			<td>Dexdomitor</td>
			<td>Orion Pharma</td>
			<td>6295000</td>
			<td>Dexmedetomidine hydrochloride</td>
		</tr>
		<tr>
			<td>EEG Analysis Software</td>
			<td>The Mathworks Inc.</td>
			<td>MATLAB R2011b</td>
			<td></td>
		</tr>
		<tr>
			<td></td>
			<td></td>
			<td>Brainstorm</td>
			<td>Sylvain et al. 2001</td>
		</tr>
		<tr>
			<td></td>
			<td></td>
			<td>OpenMEEG</td>
			<td>Bramfort et al. 2010</td>
		</tr>
		<tr>
			<td>EEG Data Streamer</td>
			<td>Tucker-Davis Technologies</td>
			<td>RS4 Data Streamer</td>
			<td></td>
		</tr>
		<tr>
			<td>EEG Electrode Paste</td>
			<td>Biotach</td>
			<td>YGB 103</td>
			<td></td>
		</tr>
		<tr>
			<td>EEG Preamplifier</td>
			<td>BioSemi</td>
			<td>Active Two</td>
			<td></td>
		</tr>
		<tr>
			<td></td>
			<td>Brain Products</td>
			<td>BrainAmp</td>
			<td></td>
		</tr>
		<tr>
			<td></td>
			<td>Tucker-Davis Technologies</td>
			<td>PZ3 Low Impedance Amplifier</td>
			<td></td>
		</tr>
		<tr>
			<td>EEG Processor</td>
			<td>Tucker-Davis Technologies</td>
			<td>RZ2 BioAmp Processor</td>
			<td></td>
		</tr>
		<tr>
			<td>EEG Recording Software</td>
			<td>Tucker-Davis Technologies</td>
			<td>OpenEx - OpenDeveloper</td>
			<td></td>
		</tr>
		<tr>
			<td>EEG SCSI Connector</td>
			<td>BioSemi</td>
			<td>Active Two SCSI Connector</td>
			<td></td>
		</tr>
		<tr>
			<td></td>
			<td>Brain Products</td>
			<td>D-sub Connector</td>
			<td></td>
		</tr>
		<tr>
			<td></td>
			<td>Tucker-Davis Technologies</td>
			<td>Zif-Clif Digital Headstage</td>
			<td></td>
		</tr>
		<tr>
			<td>High Resolution EEG Mini-cap</td>
			<td>Cortech Solutions</td>
			<td>DA-AR-ELRCS32</td>
			<td>US patent Application No. 13/641,834</td>
		</tr>
		<tr>
			<td>Isoflurane, USP</td>
			<td>VedcoPiramal Healthcare</td>
			<td>NDC 66794-013-25</td>
			<td></td>
		</tr>
		<tr>
			<td>Isopropyl Alcohol</td>
			<td>Aqua Solutions</td>
			<td>3112213</td>
			<td>90% v/v solution</td>
		</tr>
		<tr>
			<td>Lubricant Ophthalmic Ointment</td>
			<td>Rugby</td>
			<td>NDC 0536-6550-91</td>
			<td>Sterile</td>
		</tr>
		<tr>
			<td>NaCl</td>
			<td>Abbott</td>
			<td>2B8203</td>
			<td>Vaterinary 0.9% Sodium Chroride Injection USP</td>
		</tr>
		<tr>
			<td>Physiology Recording Software</td>
			<td>ADInstruments</td>
			<td>LabChart 7.0</td>
			<td></td>
		</tr>
		<tr>
			<td>Physiology Recording System</td>
			<td>ADInstruments</td>
			<td>PowerLab 8/35</td>
			<td></td>
		</tr>
		<tr>
			<td>Syringe</td>
			<td>Monoject</td>
			<td>200555</td>
			<td>12cc</td>
		</tr>
	</tbody>
</table>

brain source imaging in preclinical rat models of focal epilepsy using high-resolution eeg recordings

Electroencephalogram (EEG) has been traditionally used to determine which brain regions are the most likely candidates for resection in patients with focal epilepsy. This methodology relies on the assumption that seizures originate from the same regions of the brain from which interictal epileptiform discharges (IEDs) emerge. Preclinical models are very useful to find correlates between IED locations and the actual regions underlying seizure initiation in focal epilepsy. Rats have been commonly used in preclinical studies of epilepsy1; hence, there exist a large variety of models for focal epilepsy in this particular species. However, it is challenging to record multichannel EEG and to perform brain source imaging in such a small animal. To overcome this issue, we combine a patented-technology to obtain 32-channel EEG recordings from rodents2 and an MRI probabilistic atlas for brain anatomical structures in Wistar rats to perform brain source imaging. In this video, we introduce the procedures to acquire multichannel EEG from Wistar rats with focal cortical dysplasia, and describe the steps both to define the volume conductor model from the MRI atlas and to uniquely determine the IEDs. Finally, we validate the whole methodology by obtaining brain source images of IEDs and compare them with those obtained at different time frames during the seizure onset.

一旦所有的程序都适当地完成，估计的源可以被可视化的临床前模型的脑表面。 图5示出了从一个特定子类型尖峰（上）和从IED的尖波（底）的估计的来源。此外， 图6显示发作期间建立在连续的时间帧的源分布变化如何。这些结果支持所提出的方法的能力，以记录高分辨率脑电图对大鼠局灶性癫痫和使用记录的EEG进行来源分析。 <img alt="6视觉" src="/files/ftp_upload/52700/52700fig5.jpg" /> 的IED相对于不同簇中的尖峰（上）和尖波（底部）图5.估计脑源位置。（A）的时间序列，（B）的脑电图地形，和（C）的皮质电流酸CES。进行评价的结果，在标有一个红色垂直线（A）的一个特定的时间进行。 <a href="https://www.jove.com/files/ftp_upload/52700/52700fig5highres.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="6视觉" src="/files/ftp_upload/52700/52700fig6.jpg" /> 在检图6.大脑估算来源的时刻被标记为红色的垂直线。 <a href="https://www.jove.com/files/ftp_upload/52700/52700fig6highres.jpg" target="_blank">请点击此处查看该图的放大版本。</a>

Watch this Scientific Journal Video about Brain Source Imaging in Preclinical Rat Models of Focal Epilepsy using High-Resolution EEG Recordings at JoVE.com

Brain Source Imaging in Preclinical Rat Models of Focal Epilepsy using High-Resolution EEG Recordings

This video introduces the preparation, recording, and source analysis procedures of high-resolution EEG on sedated rats with a particular preclinical model of focal epilepsy under noninvasive conditions.

采用高分辨率脑电图记录脑源成像局灶性癫痫的临床前模型大鼠

Electroencephalogram (EEG) has been traditionally used to determine which brain regions are the most likely candidates for resection in patients with ...

brain-source-imaging-preclinical-rat-models-focal-epilepsy-using-high

Research

JoVE Journal

Medicine

15.2K 次观看.  Florida International University. This video introduces the preparation, recording, and source analysis procedures of high-resolution EEG on sedated rats with a particular preclinical model of focal epilepsy under noninvasive conditions.

视频: Brain Source Imaging in Preclinical Rat Models of Focal Epilepsy using High-Resolution EEG Recordings

MRI-guided Disruption of the Blood-brain Barrier using Transcranial Focused Ultrasound in a Rat Model

Focused ultrasound (FUS) disruption of the blood-brain barrier (BBB) is an increasingly investigated technique for circumventing the BBB1-5. The BBB is a significant obstacle to pharmaceutical treatments of brain disorders as it limits the passage of molecules from the vasculature into the brain tissue to molecules less than approximately 500 Da in size6. FUS induced BBB disruption (BBBD) is temporary and reversible4 and has an advantage over chemical means of inducing BBBD by being highly localized. FUS induced BBBD provides a means for investigating the effects of a wide range of therapeutic agents on the brain, which would not otherwise be deliverable to the tissue in sufficient concentration. While a wide range of ultrasound parameters have proven successful at disrupting the BBB2,5,7, there are several critical steps in the experimental procedure to ensure successful disruption with accurate targeting. This protocol outlines how to achieve MRI-guided FUS induced BBBD in a rat model, with a focus on the critical animal preparation and microbubble handling steps of the experiment.

Microbubble-mediated focused ultrasound disruption of the blood-brain barrier (BBB) is a promising technique for non-invasive targeted drug delivery in the brain1-3. This protocol outlines the experimental procedure for MRI-guided transcranial BBB disruption in a rat model.

MRI引导下的破坏血脑屏障在大鼠模型经颅聚焦超声

Focused ultrasound (FUS) disruption of the blood-brain barrier (BBB) is an increasingly investigated technique for circumventing the BBB1-5. The BBB is a ...

科研

医学

Segmentation and Measurement of Fat Volumes in Murine Obesity Models Using X-ray Computed Tomography

Obesity is associated with increased morbidity and mortality as well as reduced metrics in quality of life.1 Both environmental and genetic factors are associated with obesity, though the precise underlying mechanisms that contribute to the disease are currently being delineated.2,3 Several small animal models of obesity have been developed and are employed in a variety of studies.4 A critical component to these experiments involves the collection of regional and/or total animal fat content data under varied conditions.
Traditional experimental methods available for measuring fat content in small animal models of obesity include invasive (e.g. ex vivo measurement of fat deposits) and non-invasive (e.g. Dual Energy X-ray Absorptiometry (DEXA), or Magnetic Resonance (MR)) protocols, each of which presents relative trade-offs. Current invasive methods for measuring fat content may provide details for organ and region specific fat distribution, but sacrificing the subjects will preclude longitudinal assessments. Conversely, current non-invasive strategies provide limited details for organ and region specific fat distribution, but enable valuable longitudinal assessment. With the advent of dedicated small animal X-ray computed tomography (CT) systems and customized analytical procedures, both organ and region specific analysis of fat distribution and longitudinal profiling may be possible. Recent reports have validated the use of CT for in vivo longitudinal imaging of adiposity in living mice.5,6 Here we provide a modified method that allows for fat/total volume measurement, analysis and visualization utilizing the Carestream Molecular Imaging Albira CT system in conjunction with PMOD and Volview software packages.

Fat content analysis is routinely conducted in studies utilizing murine obesity models. Emerging methods in small animal CT imaging and analysis are providing for longitudinal detail rich fat content analysis. Here we detail step by step procedures for performing small animal CT imaging, analysis, and visualization.

利用X射线计算机断层扫描在小鼠肥胖模型的FAT卷的分割和测量

Obesity is associated with increased morbidity and mortality as well as reduced metrics in quality of life.1 Both environmental and genetic factors are ...

A Novel High-resolution In vivo Imaging Technique to Study the Dynamic Response of Intracranial Structures to Tumor Growth and Therapeutics

We have successfully integrated previously established Intracranial window (ICW) technology 1-4 with intravital 2-photon confocal microscopy to develop a novel platform that allows for direct long-term visualization of tissue structure changes intracranially. Imaging at a single cell resolution in a real-time fashion provides supplementary dynamic information beyond that provided by standard end-point histological analysis, which looks solely at 'snap-shot' cross sections of tissue.
Establishing this intravital imaging technique in fluorescent chimeric mice, we are able to image four fluorescent channels simultaneously. By incorporating fluorescently labeled cells, such as GFP+ bone marrow, it is possible to track the fate of these cells studying their long-term migration, integration and differentiation within tissue. Further integration of a secondary reporter cell, such as an mCherry glioma tumor line, allows for characterization of cell:cell interactions. Structural changes in the tissue microenvironment can be highlighted through the addition of intra-vital dyes and antibodies, for example CD31 tagged antibodies and Dextran molecules.
Moreover, we describe the combination of our ICW imaging model with a small animal micro-irradiator that provides stereotactic irradiation, creating a platform through which the dynamic tissue changes that occur following the administration of ionizing irradiation can be assessed.
Current limitations of our model include penetrance of the microscope, which is limited to a depth of up to 900 &mu;m from the sub cortical surface, limiting imaging to the dorsal axis of the brain. The presence of the skull bone makes the ICW a more challenging technical procedure, compared to the more established and utilized chamber models currently used to study mammary tissue and fat pads 5-7. In addition, the ICW provides many challenges when optimizing the imaging.

A Novel High-resolution In vivo Imaging Technique to Study the Dynamic Response of Intracranial Structures to Tumor Growth and Therapeutics

We describe a novel in vivo imaging technique that couples fluorescent chimeric mice with intracranial windows and high-resolution 2-photon microscopy. This imaging platform aids studies of dynamic changes in brain tissue and microvasculature, at a single-cell level, following pathological insults and is adaptable to assess intracranial drug delivery and distribution.

一种新型的高分辨率<em&gt;在体内</em&gt;成像技术研究肿瘤生长及治疗颅内结构的动态响应

We have successfully integrated previously established Intracranial window (ICW) technology 1-4 with intravital 2-photon confocal microscopy to develop a ...

MRI and PET in Mouse Models of Myocardial Infarction

Myocardial infarction is one of the leading causes of death in the Western world. The similarity of the mouse heart to the human heart has made it an ideal model for testing novel therapeutic strategies.
In vivo magnetic resonance imaging (MRI) gives excellent views of the heart noninvasively with clear anatomical detail, which can be used for accurate functional assessment. Contrast agents can provide basic measures of tissue viability but these are nonspecific. Positron emission tomography (PET) is a complementary technique that is highly specific for molecular imaging, but lacks the anatomical detail of MRI. Used together, these techniques offer a sensitive, specific and quantitative tool for the assessment of the heart in disease and recovery following treatment.
In this paper we explain how these methods are carried out in mouse models of acute myocardial infarction. The procedures described here were designed for the assessment of putative protective drug treatments. We used MRI to measure systolic function and infarct size with late gadolinium enhancement, and PET with fluorodeoxyglucose (FDG) to assess metabolic function in the infarcted region. The paper focuses on practical aspects such as slice planning, accurate gating, drug delivery, segmentation of images, and multimodal coregistration. The methods presented here achieve good repeatability and accuracy maintaining a high throughput.

We describe how to perform MRI and PET imaging of the mouse heart. The protocol is tailored to assess treatment efficacy in models of myocardial infarction and heart failure.

MRI和PET心肌梗死小鼠模型

Myocardial infarction is one of the leading causes of death in the Western world. The similarity of the mouse heart to the human heart has made it an ...

Multi-electrode Array Recordings of Human Epileptic Postoperative Cortical Tissue

Epilepsy, affecting about 1% of the population, comprises a group of neurological disorders characterized by the periodic occurrence of seizures, which disrupt normal brain function. Despite treatment with currently available antiepileptic drugs targeting neuronal functions, one third of patients with epilepsy are pharmacoresistant. In this condition, surgical resection of the brain area generating seizures remains the only alternative treatment. Studying human epileptic tissues has contributed to understand new epileptogenic mechanisms during the last 10 years. Indeed, these tissues generate spontaneous interictal epileptic discharges as well as pharmacologically-induced ictal events which can be recorded with classical electrophysiology techniques. Remarkably, multi-electrode arrays (MEAs), which are microfabricated devices embedding an array of spatially arranged microelectrodes, provide the unique opportunity to simultaneously stimulate and record field potentials, as well as action potentials of multiple neurons from different areas of the tissue. Thus MEAs recordings offer an excellent approach to study the spatio-temporal patterns of spontaneous interictal and evoked seizure-like events and the mechanisms underlying seizure onset and propagation. Here we describe how to prepare human cortical slices from surgically resected tissue and to record with MEAs interictal and ictal-like events ex vivo.

We here describe how to perform multi-electrode array recordings of human epileptic cortical tissue. Epileptic tissue resection, slice preparation and multi-electrode array recordings of interictal and ictal events are demonstrated in detail.

人类癫痫术后皮层组织的多电极阵列录音

Epilepsy, affecting about 1% of the population, comprises a group of neurological disorders characterized by the periodic occurrence of seizures, which ...

Assessing Cortical Cerebral Microinfarcts on High Resolution MR Images

Cerebral microinfarcts are frequent findings in the post-mortem human brain, and are related to cognitive decline and dementia. Due to their small sizes it is challenging to study them on clinical MRI scans. It was recently demonstrated that cortical microinfarcts can be depicted with MRI scanners using high magnetic field strengths (7T). Based on this experience, a proportion of these lesions is also visible on lower resolution 3T MRI. These findings were corroborated with ex vivo imaging of post-mortem human brain tissue, accompanied by histopathological verification of possible cortical microinfarcts.
Here an ex vivo imaging protocol is presented, for the purpose of validating MR observed cerebral microvascular pathology with histological evaluation. Furthermore, guidelines are provided for the assessment of cortical microinfarcts on both in vivo 7T and 3T MR images. These guidelines provide researchers with a tool to rate cortical microinfarcts on in vivo images of larger patient samples, to further unravel their clinical relevance in cognitive decline and dementia, and establish these lesions as a novel biomarker of cerebral small vessel disease.

A high resolution ex vivo 7T MR imaging protocol is presented, to perform MR-guided histopathological validation of microvascular pathology in post-mortem human brain tissue. Furthermore, guidelines are provided for the assessment of cortical microinfarcts on in vivo 7T as well as 3T MR images.

评估皮层脑Microinfarcts高分辨率核磁共振图像

Cerebral microinfarcts are frequent findings in the post-mortem human brain, and are related to cognitive decline and dementia. Due to their small sizes ...

A Multimodal Imaging- and Stimulation-based Method of Evaluating Connectivity-related Brain Excitability in Patients with Epilepsy

Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations over time in the blood-oxygenation level dependent signal. rs-fcMRI has been applied extensively to identify abnormalities in brain connectivity in different neurologic and psychiatric diseases. However, the relationship among rs-fcMRI connectivity abnormalities, brain electrophysiology and disease state is unknown, in part because the causal significance of alterations in functional connectivity in disease pathophysiology has not been established. Transcranial Magnetic Stimulation (TMS) is a technique that uses electromagnetic induction to noninvasively produce focal changes in cortical activity. When combined with electroencephalography (EEG), TMS can be used to assess the brain's response to external perturbations. Here we provide a protocol for combining rs-fcMRI, TMS and EEG to assess the physiologic significance of alterations in functional connectivity in patients with neuropsychiatric disease. We provide representative results from a previously published study in which rs-fcMRI was used to identify regions with abnormal connectivity in patients with epilepsy due to a malformation of cortical development, periventricular nodular heterotopia (PNH). Stimulation in patients with epilepsy resulted in abnormal TMS-evoked EEG activity relative to stimulation of the same sites in matched healthy control patients, with an abnormal increase in the late component of the TMS-evoked potential, consistent with cortical hyperexcitability. This abnormality was specific to regions with abnormal resting-state functional connectivity. Electrical source analysis in a subject with previously recorded seizures demonstrated that the origin of the abnormal TMS-evoked activity co-localized with the seizure-onset zone, suggesting the presence of an epileptogenic circuit. These results demonstrate how rs-fcMRI, TMS and EEG can be utilized together to identify and understand the physiological significance of abnormal brain connectivity in human diseases.

Resting-state functional-connectivity MRI has identified abnormalities in patients with a wide range of neuropsychiatric disorders, including epilepsy due to malformations of cortical development. Transcranial Magnetic Stimulation in combination with EEG can demonstrate that patients with epilepsy have cortical hyperexcitability in regions with abnormal connectivity.

评价中的连接有关的大脑兴奋患者癫痫多式联运Imaging-和激励为基础的方法

Resting-state functional connectivity MRI (rs-fcMRI) is a technique that identifies connectivity between different brain regions based on correlations ...

Network Analysis of Foramen Ovale Electrode Recordings in Drug-resistant Temporal Lobe Epilepsy Patients

Approximately 30% of epilepsy patients are refractory to antiepileptic drugs. In these cases, surgery is the only alternative to eliminate/control seizures. However, a significant minority of patients continues to exhibit post-operative seizures, even in those cases in which the suspected source of seizures has been correctly localized and resected. The protocol presented here combines a clinical procedure routinely employed during the pre-operative evaluation of temporal lobe epilepsy (TLE) patients with a novel technique for network analysis. The method allows for the evaluation of the temporal evolution of mesial network parameters. The bilateral insertion of foramen ovale electrodes (FOE) into the ambient cistern simultaneously records electrocortical activity at several mesial areas in the temporal lobe. Furthermore, network methodology applied to the recorded time series tracks the temporal evolution of the mesial networks both interictally and during the seizures. In this way, the presented protocol offers a unique way to visualize and quantify measures that considers the relationships between several mesial areas instead of a single area.

This protocol describes a procedure to track the evolution of mesial network measures in temporal lobe epilepsy (TLE) patients. It is based on the combination of intracranial recordings with a novel numerical technique for data analysis. Specifically, we present a protocol for network analyses of foramen ovale recordings.

在耐药性颞叶癫痫患者卵圆孔电极记录的网络分析

Approximately 30% of epilepsy patients are refractory to antiepileptic drugs. In these cases, surgery is the only alternative to eliminate/control ...

The Pilocarpine Model of Temporal Lobe Epilepsy and EEG Monitoring Using Radiotelemetry System in Mice

Temporal lobe epilepsy (TLE) is a common neurological disorder in adulthood. For translational studies of chronic epilepsy, pilocarpine-induced status epilepticus (SE) is frequently selected to recapitulate spontaneous recurrent seizures (SRS). Here we present a protocol of SE induction by intraperitoneal (i.p.) injection of pilocarpine and monitoring of chronic recurring seizures in live animals using a wireless telemetry video and electroencephalogram (EEG) system. We demonstrated notable behavioral changes that need attention after pilocarpine injection and their correlation with hippocampal neuronal loss at 7 days and 6 weeks post-pilocarpine. We also describe the experimental procedures of electrode implantation for video and EEG recording, and analysis of the frequency and duration of chronic recurrent seizures. Finally, we discuss the possible reasons why the expected results are not achieved in each case. This provides a basic overview of modeling chronic epilepsy in mice and guidelines for troubleshooting. We believe this protocol can serve as a baseline for suitable models of chronic epilepsy and epileptogenesis.

This manuscript describes a method of inducing status epilepticus by systemic pilocarpine injection and of monitoring spontaneous recurrent seizures in live animals using a wireless telemetry video and electroencephalogram system. This protocol can be utilized for studying the pathophysiologic mechanisms of chronic epilepsy, epileptogenesis, and acute seizures.

小鼠颞叶癫痫的 Radiotelemetry 模型及脑电图监测

Temporal lobe epilepsy (TLE) is a common neurological disorder in adulthood. For translational studies of chronic epilepsy, pilocarpine-induced status ...

High-Resolution Three-Dimensional Imaging of the Footpad Vasculature in a Murine Hindlimb Gangrene Model

Peripheral arterial disease (PAD) is a significant cause of morbidity resulting from chronic exposure to atherosclerotic risk factors. Patients suffering from its most severe form, chronic limb-threatening ischemia (CLTI), face substantial impairments to daily living, including chronic pain, limited walking distance without pain, and nonhealing wounds. Preclinical models have been developed in various animals to study PAD, but mouse hindlimb ischemia remains the most widely used. There can be significant variation in response to ischemic insult in these models depending on the mouse strain used and the site, number, and means of arterial disruption. This protocol describes a unique method combining femoral artery and vein electrocoagulation with the administration of a nitric oxide synthase (NOS) inhibitor to reliably induce footpad gangrene in Friend Virus B (FVB) mice that resembles the tissue loss of CLTI. While traditional means of assessing reperfusion such as laser Doppler perfusion imaging (LDPI) are still recommended, intracardiac perfusion of the lipophilic dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) is used to label the vasculature. Subsequent whole-mount confocal laser scanning microscopy allows for high-resolution, three-dimensional (3D) reconstruction of footpad vascular networks that complements traditional means of assessing reperfusion in hindlimb ischemia models.

The present protocol describes a unique, clinically relevant model of peripheral arterial disease that combines femoral artery and vein electrocoagulation with the administration of a nitric oxide synthase inhibitor to induce hindlimb gangrene in FVB mice. Intracardiac DiI perfusion is then used for high-resolution, three-dimensional imaging of the footpad vasculature.

小鼠后肢坏死模型中脚垫脉管系统的高分辨率三维成像

Peripheral arterial disease (PAD) is a significant cause of morbidity resulting from chronic exposure to atherosclerotic risk factors. Patients suffering ...