这项工作是由美国国防部高级研究计划局（DARPA）MTO杰克朱迪博士和Doug Weber博士通过空间和海战系统中心，太平洋格兰特/合同No.N66001-12-C-4173的主持下举办。我们要感谢托马斯·埃格斯他在制造过程中的帮助，罗纳德Triolo，马修·席费尔，李费舍尔和Freeburg的最大值为他们在复合神经袖口设计的发展做出贡献。

1.电极组件准备<ol><li>收集需要精密切割四级式电极组件（使用激光切割，请参考材料清单）的制造过程之前。这些组件（ 图1）: 联系方式阵列框架:这个框架是做出来的125微米厚的聚醚醚酮（PEEK）板材。它覆盖袖带的整个宽度并保持中间触点，具有蛇形边缘（ 图1B）。中间接触被包裹在所述导向通道;因此触点的暴露宽度由信道的宽度的限制和间隔由信道之间的间隔来确定。 中间接点条:中间触点由缠绕触头阵列框架（ 图1B），这些条带形成。切带出铂/ 10％铱片到引导通道的宽度和添加额外的长度，以允许他们到bË周围的框架完全折叠。在0°角条的长轴点焊联系人的领先地位。 参考联系人:需要四个引用。这些接触的长尺寸比压脉袋的宽度稍短，充分包含它们的压脉袋的内部。点焊每个参考接触到铅在90度角与该联系人的主轴线。 PEEK间隔物:间隔被用来在电极上创建较薄区域，以允许弯曲和关闭（ 图1C）。所有的间隔物从PEEK（也可使用其它材料）制成并切成电极的长度。中间空间的宽度是相等的电极的高度。 </li></ol> 2.联系人阵列的制备<ol><li>清洗在步骤1通过超声处理在乙醇中在40千赫和室温，然后在相同的超声参数在去离子蒸馏水2分钟制成2分钟的组分。让干燥。 </li><li>目视检查联系方式对于像激光切割残留或表面变形的缺陷。 </li><li>定位接触逐个与焊接点朝上，在显微镜下。保持用镊子在大约长度起点的1/3从自由端接触。提升导致一个45度角，同时保持接触，使第一弯。 </li><li>放置与焊接朝上阵列框架下方的预先弯曲的接触。按住框架下用镊子和提升领先优势扩大到一个45度角进行第二次弯曲。而继续保持架向下，抓住与镊子和弯曲的接触在一个180度的角度（朝向框的中间线折叠）的自由端。 </li><li>伸直和拉向运营商接触，然后在180度的角度（折叠中间线）弯曲。点焊点现在应该在两个弯曲端之间的封闭英寸</li><li>重复步骤2.3 - 2.5余下的联系人。让尽可能紧。交替CONTA克拉导致在阵列框架的每一侧。 </li></ol> 3.袖口布局指南<ol><li>创建袖口的平开位置的二维图。 注:使用任何CAD软件来产生一个真正的大规模图。该图将确定在电极和放置位的各种电极元件的尺寸。 </li><li>打印在普通印刷纸上的二维示意图使用普通印刷机按比例绘制，然后通过5厘米见方的片与位于中央的绘图切出5厘米。 </li><li> 5厘米见方的一块热板的透明度（T1）用手术刀切出5厘米。 </li><li>放置在图纸张的顶部的透明片T1，然后将两个层在与图朝上底板。胶带下来，用胶带底板。 </li></ol> 4.电极基础层和参考联系人布局<ol><li>切出5厘米约5cm硅胶片用手术刀（S1），并且第恩将其放置在透明层上。通过丢弃一个角然后慢慢降低的片材的其余部分，以避免在T1和S1片（ 图2A）之间捕集的气泡开始。 </li><li>混合大约2g未固化的硅的指示对制造商的数据表。两部分严格搅拌用消毒的木制搅拌粘在一起。放置在真空腔室中的混合物3分钟。循环真空，因为他们浮出水面，以消除泡沫。预热烤箱isotemp在130ºC。 注意:乳胶手套可以抑制硅的固化过程。乳胶手套还含有硫可在工作表面上留下污染物。建议使用丁腈手套代替。 </li><li>使用牙科拾取工具，应用未固化的硅的薄线沿它们所在的指导图上的间隔件段的中间。 </li><li>将垫片到指定区域，然后按下来对硅胶片S1。</li><li>部分固化在isotemp烤箱硅30分钟，让其冷却10分钟。 </li><li>将参考接触到指定区域。确保焊接点朝上，接触导线对袖口出口在远端中线路由。确保正确定位后，向下按接触到硅层S1。存未固化的硅到通孔。 </li><li>磁带走在动态再完全固化硅酮以130ºC90分钟，或在室温下过夜（ 图2B）。 </li></ol> 5.中心联系阵列布局<ol><li>切出1.5厘米约5cm透明度片用手术刀（T2）。磁带走在参考从中间区域导致远，以防止它们在下一步骤中，触点阵列下方运行。 </li><li>放置触点阵列的专用位置与引线侧朝上。沉积未固化的硅到钉阵列中地点。 </li><li>广场5.1（T2）在电极的中线并在阵列中的一块保存下来，然后用胶带将两端同时按下向下阵列。手动对齐与专用位置的阵列。大盘回落袖口的边界之外的线索。 </li><li>放置在电极的中心，并通过透明段T2中的小夹具栏。以适度的压力压向基硅氧烷层S1中的中间触头夹紧它向下到基板。 </li><li>完全固化的硅氧烷为90分钟，在130ºC，或在RT过夜。 </li></ol> 6.嵌入电极组件<ol><li>取下小灯条，轻轻取出透明板T2，露出中间触点阵列。删除所有持有两个引用和中间触点（ 图2C）导线的磁带。 </li><li>切一块方形透明片材的用手术刀的相同的宽度电极和5厘米的长度（T3），然后切一块方形硅胶片的覆盖整个电极表面（S2）。 </li><li>躺在透明度片（T3）的顶部的硅胶片（S2）及拉伸它，以除去任何波或不规则性和对被截留在两者之间消除气泡。 </li><li>切四件硅胶管; 5厘米长的每个。将它们放置在作为分配的指导图上的引线的出口部位。离开电极边缘和管&#39;的边缘之间有2毫米的空间。按住每对管用镊子，大盘回落管在1毫米开始从管端走。重复其他对。 </li><li>安排和中间触点与引用成束的导线，然后通过靠近出口部位对应的管传递它们。重复其他三个管。 （ 图2D）。 </li><li>沉积在整个电极体未固化的硅的慷慨的金额。 注:避免形成在此步骤期间由任一慢慢倾倒从抽真空的混合容器中的未固化的硅树脂或用注射器注入它红外气泡。 </li><li>放置6.3结构上与硅氧烷薄片S2朝下沉积未固化的硅的顶部。与电极对准透明度片T3同时保持硅酮片材S2粘合到它。 </li><li>大盘回落的透明度件T3，然后施加压力，以引导出任何截留气泡。放置在电极的中心，并通过透明段T3中的大的夹具杆。然后夹住它下降到中度压力底板。完全固化的硅氧烷为90分钟，在130ºC，或在RT过夜。 </li></ol> 7.屏蔽层放置（推荐录音护腕） <ol><li>如果大的夹具酒吧和分层透明片（T3）用镊子。放置屏蔽片在所述电极的每一个面的中心和施加轻微的压力吨o按他们进入电极。存未固化的硅到通孔。 </li><li>部分固化的硅氧烷在130ºC30分钟，然后让它完全冷却到室温。放置胶带在电极的外端和在闭合凸缘，以防止增加额外的未固化的硅对这些段。 </li><li>重复步骤6.6至6.8。 </li></ol> 8.切出来的成品电极<ol><li>剥离并切成使用手术刀刀片在步骤7.2中加入粘合带的顶部的过量硅氧烷，然后小心地取下胶带。 </li><li>通过硅切割出窗口通过S2层，以暴露间隔段。提取用镊子嵌入间隔段。这一步会留下空隙，形成在这些地区（原来S1）灵活的单硅胶片。 </li><li>剥离上覆盖硅酮管中的粘合带的顶部的过量硅氧烷，然后用手术刀BLAD剪E要与电极体平管。 </li><li>围绕电极的外周降低至基板。 </li><li>切出每个管对之间的三角形完全穿过底板，并在外侧以下的指导图塑造引线&#39;出口点。删除从电极体中最后一个步骤超脱所有的硅材料。 </li></ol> 9.揭露联系人和屏蔽层<ol><li>通过硅树脂层S2覆盖屏蔽层切出窗口。滑行聚丙烯缝线丝在电极基底（层S1）和在基板上脱层成品袖带电极的透明层T1之间。 </li><li>翻转电极，该中心的联系和有机硅层S1朝上，再通过基地的有机硅层S1切割出窗揭露他们。重复外部参考接触暴露宽1毫米段沿c中心ontacts。确保通孔在基准触点的两侧稳定完全嵌入电极的体内。 </li></ol> 10.焊接一个连接器连接到信息<ol><li>存款焊接物质到动态分别到连接器管脚，和然后加热并用烙铁熔化两个部分在一起。 注意:DFT引线由银核由做出来的镍钴基合金MP35N的外层包围。沉积焊料物质到这些导线需要使用特种焊剂，以允许附着到导线（请参考材料清单）。 </li></ol>

<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=Selective+stimulation+of+the+canine+hypoglossal+nerve+using+a+multi-contact+cuff+electrode.">Selective stimulation of the canine hypoglossal nerve using a multi-contact cuff electrode.</a> Ann Bio Med Eng. 32, 511-519 (2004).</li><li>Rydevik, B., Lundborg, G., Bagge, U. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+graded+compression+on+intraneural+blood+flow:+An+in+vivo+study+on+rabbit+tibial+nerve.">Effects of graded compression on intraneural blood flow: An in vivo study on rabbit tibial nerve.</a> J hand Surg. 6, 3-12 (1981).</li><li>Ogata, K., Naito, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Blood+flow+of+peripheral+nerve+effects+of+dissection,+stretching+and+compression.">Blood flow of peripheral nerve effects of dissection, stretching and compression.</a> J Hand Sur. 11, 10-14 (1986).</li><li>Boretius, T., 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+transverse+intrafascicular+multichannel+electrode+(TIME)+to+interface+with+the+peripheral+nerve.">A transverse intrafascicular multichannel electrode (TIME) to interface with the peripheral nerve.</a> Bio Sen and Bio Elec. 26, 62-69 (2010).</li><li>Stieglitz, T., Schuettler, M., Meyer, J. U., Micromachined, <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=polyimide-based+devices+for+flexible+neural+interfaces.">polyimide-based devices for flexible neural interfaces.</a> Bio Med Micro Dev. 2, 283-294 (2000).</li></ol>

作者宣称，他们没有竞争的经济利益。仅供参考在这个手稿中列出的供应商。

在这篇文章中描述的制造方法需要以确保最终箍的质量灵巧和精细运动。记录触点必须精确地在两个参考电极的中间放置。这种布局已经显示出从周围的肌肉电活动27显著减少干扰。在制造过程中的接触的相对位置的任何不平衡会降低排斥反应的压脉袋外部产生的共模干扰信号。然而，通过仔细技术很少在基准触点没有明显的不平衡进行了观察。 一些改善，到袖口的?...

与外周神经系统（PNS）的接口提供了高度处理的神经命令信号访问，因为它们前往不同结构的主体内。这些信号由分册内密闭轴突生成和由紧密接合束膜细胞包围。从神经活动产生的可测量的电势的量值，如围绕分册高电阻束膜层受神经内的各个层的阻抗。因此，两种接口方法已经依赖于相对于该束膜层，即神经束内和extrafascicular办法的记录位置被探索。内部束状的方法把各分册内的电极。这些方法的实例是犹他州阵列17，纵向帧内束状电极（LIFE）18，和横向帧内束状多通道电极（TIME）32。 ŧHESE技术可以从神经选择性地记录，但没有示出在体内 ，由于尺寸和电极12的遵守长时间，可能可靠地保留功能。 特束状办法把周围神经的触点。在这些方法中使用的压脉袋电极不损害神经束膜也不外膜，并已被证明是既从外周神经系统12记录的一个安全可靠的手段。然而，超束状方法缺乏测量单单位活动的能力 - 相比于内部束状设计。即利用神经套囊电极Neuroprosthetic应用包括下肢的激活，膀胱，隔膜，治疗慢性疼痛，神经传导阻滞，感觉反馈，并记录electroneurograms 1。潜在的应用能够利用外周神经接口包括休息O形环移动到与功能性电刺激麻痹的受害者，记录从剩余的神经运动神经元活动中被截肢者，以控制动力假肢，并与自主神经系统提供生物电子药品20接口。 一个设计实现袖口电极是平接口神经电极（FINE）21。这种设计重塑神经与较大的圆周平面的横截面相比圆形。这种设计的优点是增加了可以被放置在神经触点数目，并与选择性记录和刺激的重排的内部分册触头的附近。此外，在大型动物和人类上肢和下肢神经可以采取各种形状和由精细生成的整形不变形的神经的自然几何形状。最近的试验已经表明，细能够在恢复感觉上肢16和恢复运动中与人类功能性电刺激的下肢22。 一个箍电极的基本结构包括放置多个金属触点的神经节段的表面上，然后绝缘这些联系人用不导电袖带内的神经节段沿。为了实现这个基本结构，几种设计已经提出了在以前的研究中，包括: （1） 金属接触嵌入到的确良网格 。网状然后神经周围缠绕，将所得压脉袋的形状如下所述神经几何4,5。 （2），使用预先形刚性和非导电气缸拆分缸设计来修复神经周围的联系人。接收到该压脉袋的神经片段被整形到箍的内部几何6 - 8。 ="jove_content"&gt;（3）自卷取 ，其中触点被两绝缘层之间的封闭设计 。而与外部的未拉伸层拉伸内部层被熔化。具有不同的自然休息长度为两粘结层使最终结构以形成柔性螺旋，它包装本身周围的神经。用于这些层的材料通常都被聚9聚酰亚胺10和硅橡胶1。 （4）抵靠神经引线非绝缘部分以用作电极接触。这些线索要么编织成硅管11或硅胶套缸12成型。类似的原理，使用通过排列和融合绝缘导线以形成阵列，然后通过绝缘的开口是通过这些接合线13的中间剥一小部分制成构造的罚款。这些设计的屁股UME圆神经横截面和符合此假定神经几何。 （5） 基于弹性聚酰亚胺电极 33与由微机械加工的聚酰亚胺结构，然后整合到拉伸硅酮片材，以形成自卷绕翻边形成触点。这样的设计也假设一个圆形的神经横截面。 袖带电极应该是灵活的和自我上浆，以避免拉伸和压缩，可能会导致神经损伤3的神经。一些已知的机制，使压脉袋的电极可诱导这些影响力从邻近肌肉袖带并因此神经传输，翻边和神经的机械性能，并在压脉袋的引线过分张力之间的失配。这些安全问题导致对机械柔性组特定的设计限制，几何结构和大小1。这些标准特别challe在高接触计数精细的情况下nging因为袖口必须是在横向方向上具有相同的时间僵硬重塑神经和灵活的在纵向方向上，以防止损坏以及容纳多个联系人。自上浆螺旋设计可以容纳多个联系人袖套14，但所得到的压脉袋是稍微刚性的。柔性聚酰亚胺设计可以容纳大量的接触，但容易发生分层。导线阵列设计13产生具有扁平横截面的细，但为了保持这种几何形状的导线沿袖口生产硬表面和锋利边缘使然后不适于长期植入物的长度熔合在一起。 在这篇文章中描述的制造技术生产与可以是手工制作，精度一贯的高弹性结构的高接触密度的罚款。它采用了刚性聚合物（聚醚醚酮（PEEK）），以允许精确p触点lacement。将PEEK段在电极的中心保持扁平断面，同时保持在沿神经纵向方向柔性的。这样的设计也减小了封套的总厚度和刚度由于电极体不必是为了平坦化神经或固定触头的刚性。

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fabrication of high contact-density, flat-interface nerve electrodes for recording and stimulation applications

已经进行了许多尝试来制造多接触神经套囊电极是安全，健壮和可靠的长期neuroprosthetic应用程序。这个协议描述了一种改性圆柱形神经套囊电极的制造技术，以满足这些条件。最低计算机辅助设计与制造（CAD和CAM）技术是必要的，始终如一地生产高精度（接触位置0.51±0.04毫米），各种尺寸的袖口袖口。在空间上分布的接触和保留这种设计完成预定的几何形状的能力，精确度是两个重要的标准，以优化袖口的接口选择性录音和刺激。所提出的设计，可以在纵向方向最大化灵活性，同时保持足够的刚性，在横向方向上，通过使用材料具有不同的弹性重塑神经。袖口的横截面的扩张观察区域作为增加袖带内的压力的结果，为25％，在67毫米汞柱。该测试表明了箍的弹性和它的神经响应肿胀植入后。触点的稳定性"接口和记录品质也研究了与联系人的阻抗和信噪比度量从一个长期植入箍（7.5个月），并且观察到2.55±0.25分别kΩ和5.10±0.81分贝。

（ - 7 kHz带宽和2000总增益700赫兹）录制的神经活动与使用超β输入仪表放大器定制的前置放大器进行。与所提出的协议所制造的精细电极的一个例子示于图3。植入神经周围的精细由两个自由边缘缝合在一起完成的。的压脉袋的灵活性（ 图3B）的演示指示箍变平的神经，同时保留在纵向方向上的灵活性。 除了在纵向方向上的压脉袋的灵活性，袖带还?...

Watch this Scientific Journal Video about Fabrication of High Contact-Density, Flat-Interface Nerve Electrodes for Recording and Stimulation Applications at JoVE.com

Fabrication of High Contact-Density, Flat-Interface Nerve Electrodes for Recording and Stimulation Applications

本文提供了一个高接触密度扁平接口神经电极（FINE）的制造过程的详细描述。该电极用于记录和外周神经中选择性刺激神经活动优化。

高接触密度的制作，平面接口神经电极用于记录和刺激的应用

Many attempts have been made to manufacture multi-contact nerve cuff electrodes that are safe, robust and reliable for long term neuroprosthetic ...

fabrication-high-contact-density-flat-interface-nerve-electrodes-for

Research

JoVE Journal

Neuroscience

9.6K 次观看.  Case Western Reserve University. 本文提供了一个高接触密度扁平接口神经电极（FINE）的制造过程的详细描述。该电极用于记录和外周神经中选择性刺激神经活动优化。 

视频: Fabrication of High Contact-Density, Flat-Interface Nerve Electrodes for Recording and Stimulation Applications

High Sensitivity 5-hydroxymethylcytosine Detection in Balb/C Brain Tissue

DNA hydroxymethylation is a long known modification of DNA, but has recently become a focus in epigenetic research. Mammalian DNA is enzymatically modified at the 5th carbon position of cytosine (C) residues to 5-mC, predominately in the context of CpG dinucleotides. 5-mC is amenable to enzymatic oxidation to 5-hmC by the Tet family of enzymes, which are believed to be involved in development and disease. Currently, the biological role of 5-hmC is not fully understood, but is generating a lot of interest due to its potential as a biomarker. This is due to several groundbreaking studies identifying 5-hydroxymethylcytosine in mouse embryonic stem (ES) and neuronal cells. Research techniques, including bisulfite sequencing methods, are unable to easily distinguish between 5-mC and 5-hmC . A few protocols exist that can measure global amounts of 5-hydroxymethylcytosine in the genome, including liquid chromatography coupled with mass spectrometry analysis or thin layer chromatography of single nucleosides digested from genomic DNA. Antibodies that target 5-hydroxymethylcytosine also exist, which can be used for dot blot analysis, immunofluorescence, or precipitation of hydroxymethylated DNA, but these antibodies do not have single base resolution.In addition, resolution depends on the size of the immunoprecipitated DNA and for microarray experiments, depends on probe design. Since it is unknown exactly where 5-hydroxymethylcytosine exists in the genome or its role in epigenetic regulation, new techniques are required that can identify locus specific hydroxymethylation. The EpiMark 5-hmC and 5-mC Analysis Kit provides a solution for distinguishing between these two modifications at specific loci. The EpiMark 5-hmC and 5-mC Analysis Kit is a simple and robust method for the identification and quantitation of 5-methylcytosine and 5-hydroxymethylcytosine within a specific DNA locus. This enzymatic approach utilizes the differential methylation sensitivity of the isoschizomers MspI and HpaII in a simple 3-step protocol. Genomic DNA of interest is treated with T4-BGT, adding a glucose moeity to 5-hydroxymethylcytosine. This reaction is sequence-independent, therefore all 5-hmC will be glucosylated; unmodified or 5-mC containing DNA will not be affected. This glucosylation is then followed by restriction endonuclease digestion. MspI and HpaII recognize the same sequence (CCGG) but are sensitive to different methylation states. HpaII cleaves only a completely unmodified site: any modification (5-mC, 5-hmC or 5-ghmC) at either cytosine blocks cleavage. MspI recognizes and cleaves 5-mC and 5-hmC, but not 5-ghmC. The third part of the protocol is interrogation of the locus by PCR. As little as 20 ng of input DNA can be used. Amplification of the experimental (glucosylated and digested) and control (mock glucosylated and digested) target DNA with primers flanking a CCGG site of interest (100-200 bp) is performed. If the CpG site contains 5-hydroxymethylcytosine, a band is detected after glucosylation and digestion, but not in the non-glucosylated control reaction. Real time PCR will give an approximation of how much hydroxymethylcytosine is in this particular site. In this experiment, we will analyze the 5-hydroxymethylcytosine amount in a mouse Babl/C brain sample by end point PCR.

The EpiMark 5-hmC and 5-mC Analysis Kit can be used to analyze and quantitate 5-methylcytosine and 5-hydroxymethylcytosine within a spe cific locus. The kit distinguishes 5-mC from 5-hmC by the addition of glucose to the hydroxyl group of 5-hmC via an enzymatic reaction utilizing &beta;-glucosyltransferase (T4-BGT). When 5-hmC occurs In the context of CCGG, this modification converts a cleavable MspI site to a non-cleavable site.

BALB / C脑组织中的高灵敏度检测5 - hydroxymethylcytosine

DNA hydroxymethylation is a long known modification of DNA, but has recently become a focus in epigenetic research.   Mammalian DNA is enzymatically ...

科研

神经科学

Surgical Implantation of Chronic Neural Electrodes for Recording Single Unit Activity and Electrocorticographic Signals

The success of long-term electrophysiological recordings often depends on the quality of the implantation surgery. Here we provide useful information for surgeons who are learning the process of implanting electrode systems. We demonstrate the implantation procedure of both a penetrating and a surface electrode. The surgical process is described from start to finish, including detailed descriptions of each step throughout the procedure. It should also be noted that this video guide is focused towards procedures conducted in rodent models and other small animal models. Modifications of the described procedures are feasible for other animal models.

We provide useful information for surgeons who are learning the process of implanting chronic neural recording electrodes. Techniques for both penetrating and surface electrode systems are described in a rodent animal model.

用于记录单机活动和Electrocorticographic信号的慢性神经电极植入手术

The success of long-term electrophysiological recordings often depends on the quality of the implantation surgery.  Here we provide useful information for ...

A Method for Systematic Electrochemical and Electrophysiological Evaluation of Neural Recording Electrodes

New materials and designs for neural implants are typically tested separately, with a demonstration of performance but without reference to other implant characteristics.&#160;This precludes a rational selection of a particular implant as optimal for a particular application and the development of new materials based on the most critical performance parameters.&#160;This article develops a protocol for in vitro and in vivo testing of neural recording electrodes.&#160;Recommended parameters for electrochemical and electrophysiological testing are documented with the key steps and potential issues discussed.&#160;This method eliminates or reduces the impact of many systematic errors present in simpler in vivo testing paradigms, especially variations in electrode/neuron distance and between animal models.&#160;The result is a strong correlation between the critical in vitro and in vivo responses, such as impedance and signal-to-noise ratio.&#160;This protocol can easily be adapted to test other electrode materials and designs.&#160;The in vitro techniques can be expanded to any other nondestructive method to determine further important performance indicators.&#160;The principles used for the surgical approach in the auditory pathway can also be modified to other neural regions or tissue.

Different electrode coatings affect neural recording performance through changes to electrochemical, chemical and mechanical properties. Comparison of electrodes in vitro is relatively simple, however comparison of in vivo response is typically complicated by variations in electrode/neuron distance and between animals. This article provides a robust method to compare neural recording electrodes.

对于系统电化学神经记录电极和电生理评价方法

New materials and designs for neural implants are typically tested separately, with a demonstration of performance but without reference to other implant ...

A High Content Imaging Assay for Identification of Botulinum Neurotoxin Inhibitors

Synaptosomal-associated protein-25 (SNAP-25) is a component of the soluble NSF attachment protein receptor (SNARE) complex that is essential for synaptic neurotransmitter release. Botulinum neurotoxin serotype A (BoNT/A) is a zinc metalloprotease that blocks exocytosis of neurotransmitter by cleaving the SNAP-25 component of the SNARE complex. Currently there are no licensed medicines to treat BoNT/A poisoning after internalization of the toxin by motor neurons. The development of effective therapeutic measures to counter BoNT/A intoxication has been limited, due in part to the lack of robust high-throughput assays for screening small molecule libraries. Here we describe a high content imaging (HCI) assay with utility for identification of BoNT/A inhibitors. Initial optimization efforts focused on improving the reproducibility of inter-plate results across multiple, independent experiments. Automation of immunostaining, image acquisition, and image analysis were found to increase assay consistency and minimize variability while enabling the multiparameter evaluation of experimental compounds in a murine motor neuron system.

Botulinum neurotoxin is one of the most potent toxins among Category-A biothreat agents, yet a post-exposure therapeutic is not available. The high content imaging approach is a powerful methodology for identifying novel inhibitors as it enables multiparameter screening using biologically relevant motor neurons, the primary target of this toxin.

高含量的成像检测方法的肉毒毒素抑制剂的鉴定

Synaptosomal-associated protein-25 (SNAP-25) is a component of the soluble NSF attachment protein receptor (SNARE) complex that is essential for synaptic ...

Optogenetic Stimulation of the Auditory Nerve

Direct electrical stimulation of spiral ganglion neurons (SGNs) by cochlear implants (CIs) enables open speech comprehension in the majority of implanted deaf subjects1-6. Nonetheless, sound coding with current CIs has poor frequency and intensity resolution due to broad current spread from each electrode contact activating a large number of SGNs along the tonotopic axis of the cochlea7-9. Optical stimulation is proposed as an alternative to electrical stimulation that promises spatially more confined activation of SGNs and, hence, higher frequency resolution of coding. In recent years, direct infrared illumination of&#160;the cochlea has been used to evoke responses in the auditory nerve10. Nevertheless it requires higher energies than electrical stimulation10,11 and uncertainty remains as to the underlying mechanism12. Here we describe a method based on optogenetics to stimulate SGNs with low intensity blue light, using transgenic mice with neuronal expression of channelrhodopsin 2 (ChR2)13 or virus-mediated expression of the ChR2-variant CatCh14. We used micro-light emitting diodes (&#181;LEDs) and fiber-coupled lasers to stimulate ChR2-expressing SGNs through a small artificial opening (cochleostomy) or the round window. We assayed the responses by scalp recordings of light-evoked potentials (optogenetic auditory brainstem response: oABR) or by microelectrode recordings from the auditory pathway and compared them with acoustic and electrical stimulation.

Cochlear implants (CIs) enable hearing by direct electrical stimulation of the auditory nerve. However, poor frequency and intensity resolution limits the quality of hearing with CIs. Here we describe optogenetic stimulation of the auditory nerve in mice as an alternative strategy for auditory research and developing future CIs.

听觉神经的光遗传学刺激

Direct electrical stimulation of spiral ganglion neurons (SGNs) by cochlear implants (CIs) enables open speech comprehension in the majority of implanted ...

Assessment of Neuromuscular Function Using Percutaneous Electrical Nerve Stimulation

Percutaneous electrical nerve stimulation is a non-invasive method commonly used to evaluate neuromuscular function from brain to muscle (supra-spinal, spinal and peripheral levels). The present protocol describes how this method can be used to stimulate the posterior tibial nerve that activates plantar flexor muscles. Percutaneous electrical nerve stimulation consists of inducing an electrical stimulus to a motor nerve to evoke a muscular response. Direct (M-wave) and/or indirect (H-reflex) electrophysiological responses can be recorded at rest using surface electromyography. Mechanical (twitch torque) responses can be quantified with a force/torque ergometer. M-wave and twitch torque reflect neuromuscular transmission and excitation-contraction coupling, whereas H-reflex provides an index of spinal excitability. EMG activity and mechanical (superimposed twitch) responses can also be recorded during maximal voluntary contractions to evaluate voluntary activation level. Percutaneous nerve stimulation provides an assessment of neuromuscular function in humans, and is highly beneficial especially for studies evaluating neuromuscular plasticity following acute (fatigue) or chronic (training/detraining) exercise.

We present a protocol to assess changes in neuromuscular function. Percutaneous electrical nerve stimulation is a non-invasive method that evokes muscular responses. Electrophysiological and mechanical properties of these responses permit the evaluation of neuromuscular function from brain to muscle (supra-spinal, spinal and peripheral levels).

神经肌肉功能的应用经皮神经电刺激评估

Percutaneous electrical nerve stimulation is a non-invasive method commonly used to evaluate neuromuscular function from brain to muscle (supra-spinal, ...

Microelectrode Guided Implantation of Electrodes into the Subthalamic Nucleus of Rats for Long-term Deep Brain Stimulation

Deep brain stimulation (DBS) is a widely used and effective therapy for several neurologic disorders, such as idiopathic Parkinson&#8217;s disease, dystonia or tremor. DBS is based on the delivery of electrical stimuli to specific deep anatomic structures of the central nervous system. However, the mechanisms underlying the effect of DBS remain enigmatic. This has led to an interest in investigating the impact of DBS in animal models, especially in rats. As DBS is a long-term therapy, research should be focused on molecular-genetic changes of neural circuits that occur several weeks after DBS. Long-term DBS in rats is challenging because the rats move around in their cage, which causes problems in keeping in place the wire leading from the head of the animal to the stimulator. Furthermore, target structures for stimulation in the rat brain are small and therefore electrodes cannot easily be placed at the required position. Thus, a set-up for long-lasting stimulation of rats using platinum/iridium electrodes with an impedance of about 1 M&#937; was developed for this study. An electrode with these specifications allows for not only adequate stimulation but also recording of deep brain structures to identify the target area for DBS. In our set-up, an electrode with a plug for the wire was embedded in dental cement with four anchoring screws secured onto the skull. The wire from the plug to the stimulator was protected by a stainless-steel spring. A swivel was connected to the circuit to prevent the wire from becoming tangled. Overall, this stimulation set-up offers a high degree of free mobility for the rat and enables the head plug, as well as the wire connection between the plug and the stimulator, to retain long-lasting strength.

A method for implanting electrodes into the subthalamic nucleus (STN) of rats is described. Better localization of the STN was achieved by using a microrecording system. Furthermore, a stimulation set-up is presented that is characterized by long-lasting connections between the head of the animal and the stimulator.

微电极引导电极植入到大鼠丘脑底核的长期深部脑刺激

Deep brain stimulation (DBS) is a widely used and effective therapy for several neurologic disorders, such as idiopathic Parkinson&#8217;s disease, ...

Fabrication of Fine Electrodes on the Tip of Hypodermic Needle Using Photoresist Spray Coating and Flexible Photomask for Biomedical Applications

We have introduced a fabrication method for electrical impedance spectroscopy (EIS)-on-a-needle (EoN: EIS-on-a-needle) to locate target tissues in the body by measuring and analyzing differences in the electrical impedance between dissimilar biotissues. This paper describes the fabrication method of fine interdigitated electrodes (IDEs) at the tip of a hypodermic needle using a photoresist spray coating and flexible film photomask in the photolithography process. A polyethylene terephthalate (PET) heat shrink tube (HST) with a wall thickness of 25 &#181;m is employed as the insulation and passivation layer. The PET HST shows a higher mechanical durability compared with poly(p-xylylene) polymers, which have been widely used as a dielectric coating material. Furthermore, the HST shows good chemical resistance to most acids and bases, which is advantageous for limiting chemical damage to the EoN. The use of the EoN is especially preferred for the characterization of chemicals/biomaterials or fabrication using acidic/basic chemicals. The fabricated gap and width of the IDEs are as small as 20 &#181;m, and the overall width and length of the IDEs are 400 &#181;m and 860 &#181;m, respectively. The fabrication margin from the tip (distance between the tip of hypodermic needle and starting point of the IDEs) of the hypodermic needle is as small as 680 &#181;m, which indicates that unnecessarily excessive invasion into biotissues can be avoided during the electrical impedance measurement. The EoN has a high potential for clinical use, such as for thyroid biopsies and anesthesia drug delivery in a spinal space. Further, even in surgery that involves the partial resection of tumors, the EoN can be employed to preserve as much normal tissue as possible by detecting the surgical margin (normal tissue that is removed with the surgical excision of a tumor) between the normal and lesion tissues.

The fabrication method for fine interdigitated electrodes (gap and width: 20 &#181;m) at the tip of a hypodermic needle (diameter: 720 &#181;m) is demonstrated using a spray coating and flexible film photomask in the photolithography process.

用光刻胶喷涂和柔性掩制备医用注射用针尖上的微细电极

We have introduced a fabrication method for electrical impedance spectroscopy (EIS)-on-a-needle (EoN: EIS-on-a-needle) to locate target tissues in the ...

Chronic Transcranial Electrical Stimulation and Intracortical Recording in Rats

Transcranial electrical stimulation (TES) is a powerful and relatively simple approach to diffusely influence brain activity either randomly or in a closed-loop event-triggered manner. Although many studies are focusing on the possible benefits and side-effects of TES in healthy and pathologic brains, there are still many fundamental open questions regarding the mechanism of action of the stimulation. Therefore, there is a clear need for a robust and reproducible method to test the acute and the chronic effects of TES in rodents. TES can be combined with regular behavioral, electrophysiological, and imaging techniques to investigate neuronal networks in vivo. The implantation of transcranial stimulation electrodes does not impose extra constraints on the experimental design while it offers a versatile, flexible tool to manipulate brain activity. Here we provide a detailed, step-by-step protocol to fabricate and implant transcranial stimulation electrodes to influence brain activity in a temporally constrained manner for months.

This detailed protocol describes transcranial stimulation electrode placement on the temporal bone in order to investigate the short- and long-term effects of transcranial electrical stimulation in freely moving rats.

大鼠慢性经颅电刺激及 Intracortical 记录

Transcranial electrical stimulation (TES) is a powerful and relatively simple approach to diffusely influence brain activity either randomly or in a ...

Ethanol-Induced Cervical Sympathetic Ganglion Block Applications for Promoting Canine Inferior Alveolar Nerve Regeneration Using an Artificial Nerve

Polyglycolic acid collagen (PGA-C) tubes are bio-absorbable nerve tubes filled with collagen of multi-chamber structure, which consist of thin collagen films. Favorable clinical outcomes have been achieved when using these tubes for the treatment of damaged inferior alveolar nerve (IAN). A critical factor for the successful nerve regeneration using PGA-C tubes is blood supply to the surrounding tissue. Cervical sympathetic ganglion block (CSGB) creates a sympathetic blockade in the head and neck region thus increasing blood flow in the area. To ensure an adequate effect, the blockade must be administered with local anesthetics one to two times a day for several consecutive weeks; this poses a challenge when creating animal models for investigating this technique. To address this limitation, we developed an ethanol-induced CSGB in a canine model of long-term increase in blood flow in the orofacial region. We examined whether IAN regeneration via PGA-C tube implantation can be enhanced by this model. Fourteen Beagles were each implanted with a PGA-C tube across a 10-mm gap in the left IAN. The IAN is located within the mandibular canal surrounded by bone, therefore we chose piezoelectric surgery, consisting of ultrasonic waves, for bone processing, in order to minimize the risk of nerve and vessel injury. A good surgical outcome was obtained with this approach. A week after surgery, seven of these dogs were subjected to left CSGB by injection of ethanol. Ethanol-induced CSGB resulted in improved nerve regeneration, suggesting that the increased blood flow effectively promotes nerve regeneration in IAN defects. This canine model can contribute to further research on the long-term effects of CSGB.

We evaluated the effect of cervical sympathetic ganglion block on nerve repair using artificial nerve conduits. Male beagle dogs were each implanted with an artificial nerve across a 10-mm gap in the left inferior alveolar nerve; left cervical sympathetic ganglion was blocked by injecting 99.5% ethanol via lateral thoracotomy.

乙醇诱导的颈椎交交型神经节阻滞在促进犬下肺泡神经再生中的应用

Polyglycolic acid collagen (PGA-C) tubes are bio-absorbable nerve tubes filled with collagen of multi-chamber structure, which consist of thin collagen ...