The authors would like to thank Dr. Christina Ginkel (German Center for Neurodegenerative Diseases, DZNE) and Dr. Robert Stark (DZNE) for their assistance with animal breeding and animal healthcare. This work was financially supported by the Federal Institute for Drugs and Medical Devices (Bundesinstitut f&#252;r Arzneimittel und Medizinprodukte, BfArM), Bonn, Germany.

所有的动物实验是根据当地和机构理事会关于动物保健（波恩大学，BfArM，LANUV，德国）的指导方针进行。此外，所有的动物实验是按照上级的立法， 如 1986年11月24日（86/609 / EEC）的欧洲共同体理事会指令，或个别区域或国家的法律进行。具体的努力是为了最大限度地减少使用的动物的数量，以及它们的痛苦。 1.动物住房和脑电图记录条件<ol><li>家鼠过滤器顶笼或使用独立通风笼。 </li><li>从动物设施在特殊的实验室室，适合植入动物和遥测记录传输小鼠通风机箱。 </li><li>执行所有动物实验，包括脑电图电极的植入和随后的录音，标准条件（22℃透射电镜023，12小时/ 12小时明-暗循环，50％-60％的相对湿度，噪声衰减等 ）18。 </li><li>之前射频发射机注入，房子的动物中的3组- 4清楚II型聚碳酸酯笼子，食物和水随意 。不要分离单个老鼠，因为这可能导致紧张和随后的实验和结果产生干扰。 </li><li>不要使用开放式的住房条件，但实验和录制过程中，而使用通风机箱。 </li></ol> 2.无线电遥测脑电图植入电极和脑电图记录<ol><li> 麻醉用注射麻醉剂， 例如，ketaminehydrochloride / xylazinehydrochloride（100/10毫克/千克，腹膜内，IP）或吸入麻醉剂， 如异氟烷17,18小鼠。 <ol><li>对于异氟烷麻醉，将鼠标定位到一个感应Çhamber用4-5％异氟醚和0.8-1％的氧气或卡波金（5％CO 2和95％O 2）。 </li><li>放置一个硅面罩上的动物，以控制麻醉的期望深度，并使用清除系统避免实验者暴露于异氟醚的鼻/口。 </li><li>使用注射麻醉剂， 如 esketaminhydrochloride（100毫克/千克，IP）和xylazinehydrochloride（10毫克/千克，IP），如果吸入麻醉不可用。 </li><li>通过检查尾巴捏反射，脚捏反射和呼吸速率监测麻醉深度。注意， 经由气管插管进行人工呼吸不在小鼠中必要的。 </li></ol></li><li> 植入射频发射机插入动物背部皮下袋。 <ol><li>从头皮去除体毛和具有两个消毒剂， 即 70％的乙醇和碘基擦洗预处理剃头皮。 </li><li>使用手术刀，使从前额到nucheal区域头皮中线切开。 </li><li>从颈部切口开始，通过使用外科剪刀或外科手术探针进行钝器解剖准备在动物背部的一侧的皮下袋中。 </li><li>将发射器放入皮下囊和灵活的发射器通向袋，以及存放多余的长度。要特别注意防止手术部位和发射器植入物的污染。正确地隔离使用窗帘非无菌区无菌。 </li></ol></li><li>将实验动物的立体框架， 例如，一个计算机化的3D立体设备。修正了使用鼻夹和耳棒头骨。 </li><li>预处理用0.3％ 的 H 2 O 2的头骨从头骨移除进一步的组织并照亮颅缝和craniometrics地标，前囟和lambda。 </li><li>在选择的坐标钻孔在以最大速度的无压模式下使用一个高速神经外科钻（参见步骤2.6）。 注:无压力钻井避免钻头和损坏皮质的突然突破。对于开颅手术，建议神经外科高速电钻。选择的0.3标准钻头直径 - 0.5毫米，这取决于电极的直径。 </li><li>慎重选择电极型，考虑到阻抗，直径，涂料等。 注:聚对二甲苯被覆钨或不锈钢电极是最常见的。电极类型应根据实验要求来选择。作为一个先发制人的手法，用消毒70％乙醇植入前电极头。注意，电极涂覆不允许用于加热消毒。 </li><li>对于海马CA1脑电图记录，在以下坐标立体定向钻孔:前囟门，-2毫米;中侧，1.5毫米（右半球）;背腹，1.3毫米（圆盾ŧ地区:大角ammonis（CA1）锥体细胞层）。为参考电极，在以下立体坐标钻小脑皮层以上的孔:前囟，-6.2毫米，中侧0毫米;背腹0毫米。 注:小脑电极用作pseudoreference电极，如小脑是一个相当无声大脑区域。立体定位坐标被从标准鼠标脑图谱而得。 </li><li>到电极的插入之前，将它们缩短到所需长度。机械地夹在电极到发射器的不锈钢螺旋的颅外一部分。 注:焊接应尽量避免，因为这会在系统中引入大量噪声。 </li><li>该电极连接到立体定位装置的垂直臂和根据上述立体坐标插入电极。 </li><li>采用固定玻璃离子水门汀电极，等到水泥已经完全硬化。 </li><li>关闭头皮使用过和悬停缝线用非可吸收的5-0或6-0缝合材料。 </li><li>对于术后疼痛管理，管理卡洛芬（5毫克/千克，皮下，SC），每日一次，连续4天，植入后。需要注意的是卡布洛芬应在首次切口（步骤2.2.2）注入。 </li><li>让动物10恢复 - 录音和/或注塑实验开始前14天植入后。 </li></ol> 3.西塔振荡与药理诱导的自发录音<ol><li>激活使用磁性开关的射频发射机。放置动物与接收器上的板其家笼。至少24-48小时进行长期海马脑电图记录。 注:脑电图振幅和长期记录脑电图频率特性的分析提供了详细的洞察成θ振荡的昼夜依赖性以及它们与特定行为和关联认知条件/任务。始终结合脑电图记录与实验动物的视频监控。 </li><li>为THETA振荡药理感应，辖氨基甲酸酯（800毫克/千克IP）或毒蕈碱受体激动剂的单一剂量，例如毛果芸香碱（10毫克/千克IP），槟榔碱（0.3毫克/千克IP）或氧化震颤素的单剂量（0.03毫克/千克IP）。预处理与N-甲基东（0.5毫克/千克IP）的小鼠，以避免外周毒蕈碱反应。新鲜溶解在0.9％NaCl或林格氏液所有药物。 注:更高的毒蕈碱受体激动剂的剂量可能导致癫痫发作感应的实验动物。同时认为，这里给出的剂量表示需要在受调查的鼠标线前剂量 - 效应研究的里程碑。注意，聚氨酯是需要在储存和处理适当的预防措施诱变剂和致癌物质。 </li><li>注射阿托品（50毫克/千克，IP）来区分阿托品敏感型II从阿托品不敏感型我THETA振荡。 注:阿托品用量为一次物种和应变依赖和需要事先剂量 - 效应评价。阿托品注射液的最佳时间点取决于毒蕈碱受体激动剂的药效学。 II型theta的识别，阿托品注射氨基甲酸酯给药后1小时，建议。 </li><li>尽量避免的几种药物的后续申请，如全身性药物施用改变全局转录和翻译模式，这影响后续脑电图记录。需要注意的是短暂的振荡THETA也可以通过感官刺激诱发，如tail-或爪子捏。 </li><li>萃取物/出口代表脑电图数据集的前阶段（基线），并从总的脑电图记录作为ASCI或TXT文件后喷射阶段的，考虑到所施加的药物的药代动力学和个体研究协议的要求。 </li></ol> 4。脑电图电极放置的验证<ol><li>通过将它们放置在一个孵育室安乐死的动物和引入100％的二氧化碳。使用的每与加入到孵育室的现有空气二氧化碳分腔室容积的10-30％的填充率;这将导致以最小的应力给动物迅速失去知觉。 </li><li>从室中取出鼠标一旦出现呼吸停止，暗淡的眼睛颜色持续2-3分钟。 </li><li>切不锈钢电极和外植体射频发射器。用剪刀或者断头台斩首鼠标轻轻操纵手术剪刀和镊子取出从脑颅大脑。 </li><li>固定在4％低聚甲醛的大脑在磷酸盐缓冲盐水（PBS）（pH 7.4）中过夜。对于冷冻保护，在4℃的大脑转移到30％的葡萄糖，并将其储存，直到进一步处理。 注意:多聚甲醛是由2012 OSHA哈兹认为是有害的ARD通信标准（29 CFR 1910.1200）。采取必要的预防措施:使用个人防护用品，保证适当的通风，避免形成粉尘。此外，除去火源，并采取防止静电放电的措施。低聚甲醛不应该被释放到环境中。 </li><li>安装在使用粘接剂的低温恒温器的组织保持器所提取的脑切大脑成40 - 75微米的冠状切片。安装片到玻片上，并使用标准的组织学方法与尼氏蓝染色他们。这个过程将可视化反映的是前电极位置的分支通道。请注意，它也有可能使用vibroslicer从天然脑切冠状切片</li><li>只合并那些符合正确的脑电图电极放置标准的动物;对于CA1区，深电极的尖端应该CA1区锥体细胞层内进行本地化。 </li></ol><ol><li>记录CA1海马脑电图与没有先验滤波器截止适当的采样速率。 注:采样速率，这是发射器 - 特异性的，确定脑电图分析的频率上限。 </li><li>处理与分析软件的记录的数据。程序的时间-频率分析，并与用于分析方法的适当的控制（ 图5）20定做程序计算。 </li><li>切断记录脑电图段用各1小时的长度。使用快速计算机处理器，因为计算时间是很高的。此外，利用软件，可以在多个内核并行20计算。 </li></ol> 6.脑电图数据分析<ol><li>分析使用复杂Morlet小波来计算的频率和振荡的振幅数据段。 注:此小波（ 例如，Ψ（X）=（πB）（ - 1/2）EXP（2 Iπçx）的EXP（-x 2 / b）中 ，其中b是带宽参数，c中的中心频率，和我虚数单位）经常在文献中研究脑电图被应用数据，因为它保证了在频率和时间两者23,24最佳分辨率。 </li><li>使用带宽参数和中心频率设置，尤其是权重，同时还不能忽略足够的时间分辨率，频率分辨率，以区分在0.1赫兹级频率的差异。 注:伽玛带神经过程是短暂的25，这也可以容纳如此THETA节奏。因此，分析方法必须考虑足够的时间分辨率。 </li><li>在0.2的频率范围分析的EEG数据 - 12赫兹，0.1 Hz的步长，因此包括典型的增量，该TA，和α的频率范围。 </li><li>设立的θ频率架构的论述，这可以代替THETA振荡的标准目视检查的自动化，复杂的分析用具;此过程被称为的θ的检测方法（TDM）的。 </li><li>计算中的θ频率范围（3.5-8.5赫兹）的最大振幅的商并且在上三角频率范围为每2.5秒的时间窗的最大振幅（2-3.4赫兹）。 注:此商数的值用作度量来决定，如果发生了theta电振荡。的θ频率范围的定义可以根据不同的功能状态和神经解剖学电路/系统上进行分析而变化。 </li><li>分类段为"THETA振荡时期，"如果这部分期间计算出的比例是1.5以上。 注意:这保证了最大THETA振幅相关2.5 - S的脑电图期间比在上部三角形带的幅度高至少50％的分割。注意，该比率可能取决于所用的线路和/或物种需要适应。的2.5秒的时间间隔表示为一个theta电振荡的最小持续时间，防止某些嘈杂历元的假阳性检测，并位于其他出版物19，26的范围定义内。上部三角形的频率范围作为控制频带因为慢波睡眠，这是THETA活动期间高度衰减期间在非-θ时期出现生理学相关的增量活性，例如，。 </li><li>重复此过程，每1小时部分;因此，每一个部分包括与每2.5秒长度1,440脑电图段。 </li><li>统计学评估所识别THETA振荡历元中的数据。 </li><li>计算检测THETA历元的总持续时间的统计信息;不同的或预定义的组;循环，如光/暗;和其他参数。 注:为staticSTICS可以包括t-检验，ANOVA，或MANOVA，取决于变量，组的数量，条件等 </li><li>计算所检测THETA历元的幅度的统计数据，但是只在的θ的频率范围（3.5 - 8.5赫兹）。 </li><li>评估所检测THETA历元的频率的统计数据，但是只在的θ的频率范围（3.5 - 8.5赫兹）。 注意:一THETA划时代的THETA频率被定义为属于一个THETA划时代的最大THETA振幅的频率。 </li></ol>

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E., Kramis, R. C., Vanderwolf, C. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Two+types+of+cerebral+activation+during+active+sleep:+relations+to+behavior.">Two types of cerebral activation during active sleep: relations to behavior.</a> Brain Res. 124, 544-549 (1977).</li></ol>

The authors have nothing to disclose.

西塔活动是全身神经生理学中心的相关性。它可以在各种脑区域可以观察到，特别是在海马，在那里它与特定行为和认知状态。此外，海马THETA可以药理分化成阿托品敏感的II型和阿托品不敏感型我THETA。 I型被认为是涉及到运动，如走路或跑步27，28，29，30，31，而II型可在警报的状态不动27，28，29，30中被观察到。报警-不动状态可以通过频繁和随机音调或触觉刺激诱发，例如32。 II型THETA还涉及巴ssive全身旋转14。在异相睡眠，无论是阿托品敏感和耐药阿托品-θ节律存在33。在静息状态下不动的特点是大的不规则活动（LIA）27。 一般来说，θ-振荡可以自发的条件下进行记录，而且以下的药理感应（ 例如， 通过毒蕈碱性受体激动剂，如氨基甲酸乙酯的应用，毛果芸香碱，槟榔碱，氧化震颤素， 等等 ）。需要注意的是，药效学，氨基甲酸酯是多目标药物可以增强II型THETA还能抑制I型2θ。与此相反，毛果芸香碱，槟榔碱，和氧化震颤素选择性诱导II型2θ。根据所使用的毒蕈碱激动剂的药物动力学，它需要的时间可变数量直到THETA振荡发生。 II型能有效被阿托品阻断。重要的是，该做的毒蕈碱激动剂和拮抗剂的先贤以诱导和块II型THETA振荡是物种和应变依赖性。因此，这是绝对必要执行剂量效应研究，以解开的最佳剂量为THETA振荡的诱导和其堵塞用于特定的科学问题。短时THETA振荡也可以通过感觉刺激，例如tail-或爪夹住来诱导。 有一般表征THETA活动不同的方法。基于FFT的方法，导致在连续或不连续（频带相关的）功率谱密度（PSD）分析/图或在为各个频带的功率分析，是提供对频率特性的有价值的信息标准的方法。 但是，为了实现更复杂的洞察成θ结构，附加的方法似乎是必要的。特别是，人们可能会喜欢不同的器官的θizational状态和它们的频率，这不能由上述程序直接和准确的评估。与此相反，这里提出的新颖的分析技术是基于小波的和能够评估高度组织，短期THETA振荡。它们不对应于标准THETA功率，这也认为阵发性的，不连续THETA活性。重点是在是典型的THETA时代脑电图数据，征求具体时间频率特性。因此，新的方法可以防止THETA时代的假阳性分类。自动化的过程保证了持久的脑电数据集的评估，因此包括在长期研究生理周期（光/暗周期或昼夜节律）的可靠的统计比较。 这个协议是特别重要的，从神经变性疾病的动物模型中得到的脑电图数据的分析，特别是在characteri在septohippocampal高度组织THETA建筑等神经系统zation。复杂和高精度THETA分析可能有助于确定EEG的指纹，可以作为在未来脑电生物标志物。

睡在大脑中的Theta活动涉及到不同的认知和功能状态，包括觉醒，注意，随意运动，探索行为，注意力的行为，学习和记忆，体感集成和快速眼动（REM）1，2。原则上，可以在不同的脑区中产生THETA活动作为一个有节奏的实体，高度组织化和同步，THETA振荡。下面，我们将集中于THETA活动/被所述septohippocampal系统3,4内产生振荡的分析和定量。内的隔膜，GABA能，谷氨酸，和胆碱能神经元投射到海马和有助于THETA振荡行为的启动和维护。有对海马THETA振荡是否在隔发起的， 即一个持续的讨论， </em&gt;隔起搏器海马跟随模式，（extrahippocampal理论）或本质海马内（海马理论）5，6，7。 不论其来源，海马THETA振荡已经在感兴趣的焦点多年来，尤其是在转基因小鼠模型。这些模型允许深脑电图电极的植入和在特定的认知和行为的任务8海马THETA振荡的记录。海马THETA振荡是在自然界中异源。根据THETA振荡的所谓的二元论，可以阿托品敏感的II型theta和阿托品不敏感的I型THETA 9，10，11之间区分。后者通常可以通过毒蕈碱诱导1 / M <sUB&gt; 3受体激动剂， 如槟榔碱，毛果芸香碱和聚氨酯。然而，氨基甲酸乙酯是一种多目标药物，除了毒蕈碱活化，也施加在其它离子通道实体复杂的影响。 II型THETA，所述毒蕈碱性通路包括M 1的活化/ M 3和随后ģQ / 11（Gα）磷脂酶C介导的活化β1/4（PLCβ1/4），三磷酸肌醇（INSP 3） ，diacylglycerole（DAG），钙离子 ，和蛋白激酶C（PKC）。 PLCβ1和PLCβ4的thetagenesis的作用已在敲除研究使用被验证PLCβ1 - / -和PLCβ4 - / -呈现THETA振荡12，13，14的完全丧失或显著衰减的小鼠。附加M 1，M 3和M 5下游目标（CHA毒蕈碱信令级联nnels /电流）包括各种电导，诸如经由电压依赖性K +通道（K 7节 ）M型K +通道（K M）;超极化K +通道（KS AHP）后慢;泄漏K +通道（K 泄漏 ），可能通过TWIK相关酸敏感的K +通道（TASK1 / 3）;阳离子电流（I CAT），可能通过钠泄漏通道（NALCN）;并经由超极化和环核苷酸门控通道（HCN）我小时 。此外，M 2 / M 4乙酰胆碱受体（乙酰胆碱受体）报告，其中内向整流干扰K +通道3.1（K IR 3.1）和内向整流钾通道3.2（K IR 3.2）15。 目前，市售的分析软件允许快速基于FFT的频率分析， 例如，功率分析（P，毫伏2）或功率谱密度（PSD，毫伏2 /赫兹）。电源或θ波频率范围内的功率谱密度（PSD）的分析只给其活动的全球概览。然而，为了得到详细的洞察认知和行为相关的THETA活性，高度组织THETA振荡的分析是强制性的。高度组织THETA振荡的评估是在神经变性和神经精神性疾病的领域重要性。最具实验性的疾病的研究都使用高度复杂的神经外科手术的方法来记录硬膜外表层和深层颅内脑电图转基因小鼠模型进行的。这些技术包括系绳系统16和无线电遥测设置17,18。西塔振荡可以记录为长期的录音条件下的自发和行为相关的THETA振荡。此外，THETA振荡可以RECOrded以下的药理感应而且下列动物暴露于行为或认知任务或感觉刺激，例如尾部夹持。 早期方法来表征THETA振荡被Csicsvari 等人所述。 19。作者设计为短期THETA分析的半自动化的工具 - 即不适合长时间脑电图记录（15 50分钟）。我们的方法中，这里描述的，允许长期脑电图记录&gt; 48小时20进行的分析。 Csicsvari 等。 10还提到了THETA三角洲率，但提供了高度组织THETA振荡的决心没有门槛。三角洲和θ范围定义符合我们的频率范围的定义。因为它是不明确提到，我们假设基于FFT的方法用于由Csicsvari 等。计算的θ-Δ频带的功率。这个再次从我们的方法明显不同，因为我们计算上的大量频率尺度（频率步骤Δ（F）= 0.05赫兹）基于小波的振幅，导致高得多的精度。独具一格的分析脑电图时代的持续时间是类似于我们的定义。 Klausberger 等。 21也借助THETA三角比长期脑电图记录的分析。但是，也有相对于我们的方法三大差别:i）所述脑电图历元持续时间要长得多， 即至少为6秒; ⅱ）的θ-Δ比设定为4，这是比我们阈高得多，并涉及到不同的频率范围定义;和iii）电源定义很可能是基于FFT的方法，它缺乏精度高，特别是对于非常短的时间窗口（2秒， 即，5个循环为2.5赫兹的频率）振荡。在这种情况下，一个基于小波的过程是更可取的。由卡普兰等人的研究。 22只计算THETA功率而忽略了THETA三角洲功率比。因此，卡普兰接近22不能伴随着高或低的增量认知丰富THETA流程进行区分。 在下面的协议，我们将提出我们的分析基于小波变换的方法来可靠地分析海马脑电图记录高度组织THETA振荡小鼠。由于该过程自动工作，它可以应用到大型数据集和长期EEG测量。

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Carprofen (Rimadyl VET - Injektionsl&#246;sung)</td>
			<td>Pfizer</td>
			<td>PZN 0110208208</td>
			<td>20ml</td>
		</tr>
		<tr>
			<td>binocular surgical magnification microscope</td>
			<td>Zeiss Stemi 2000</td>
			<td>0000001003877, 4355400000000, 0000001063306, 4170530000000, 4170959255000, 4551820000000, 4170959040000, 4170959050000</td>
		</tr>
		<tr>
			<td>Dexpanthenole (Bepanthen Wund- und Heilsalbe)</td>
			<td>Bayer</td>
			<td>PZN: 1578818</td>
			<td></td>
		</tr>
		<tr>
			<td>drapes (sterile)</td>
			<td>Hartmann</td>
			<td>PZN 0366787</td>
			<td></td>
		</tr>
		<tr>
			<td>70% ethanol</td>
			<td>Carl Roth</td>
			<td>9065.5</td>
			<td></td>
		</tr>
		<tr>
			<td>0.3% / 3% hydrogene peroxide solution</td>
			<td>Sigma</td>
			<td>95321</td>
			<td>30% stock solution</td>
		</tr>
		<tr>
			<td>gloves (sterile)</td>
			<td>Unigloves</td>
			<td>1570</td>
			<td></td>
		</tr>
		<tr>
			<td>dental glas ionomer cement</td>
			<td>KentDental /NORDENTA</td>
			<td>957 321</td>
			<td></td>
		</tr>
		<tr>
			<td>heat-based surgical instrument sterilizer</td>
			<td>F.S.T.</td>
			<td>18000-50</td>
			<td></td>
		</tr>
		<tr>
			<td>high-speed dental drill</td>
			<td>Adeor</td>
			<td>SI-1708</td>
			<td></td>
		</tr>
		<tr>
			<td>Inhalation narcotic system (isoflurane)</td>
			<td>Harvard Apparatus GmbH</td>
			<td>34-1352, 10-1340, 34-0422, 34-1041, 34-0401, 34-1067, 72-3044, 34-0426, 34-0387, 34-0415, 69-0230</td>
		</tr>
		<tr>
			<td>Isoflurane</td>
			<td>Baxter 250 ml</td>
			<td>PZN 6497131</td>
			<td></td>
		</tr>
		<tr>
			<td>Ketamine</td>
			<td>Pfizer</td>
			<td>PZN 07506004</td>
			<td></td>
		</tr>
		<tr>
			<td>Lactated Ringer&#39;s solution (sterile)</td>
			<td>Braun</td>
			<td>L7502</td>
			<td></td>
		</tr>
		<tr>
			<td>Nissl staining solution</td>
			<td>Armin Baack</td>
			<td>BAA31712159</td>
			<td></td>
		</tr>
		<tr>
			<td>pads (sterile)</td>
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			<td>(Stereo Drive-New Motorized Stereotaxic)</td>
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			<td>Radiofrequency transmitter 3.9 g, 1.9 cc, input voltage range &#177; 2.5 mV, channel bandwidth (B) 1-200 Hz, nominal sampling rate (f) 1000 Hz (f = 5B) temperature operating range 34-41 &#176;C warranted battery life 4 months</td>
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			<td>TL11M2-F20EET</td>
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			<td>Radiofrequency transmitter 3.9 g, 1.9 cc, input voltage range &#177; 1.25 mV, channel bandwidth (B) 1-50 Hz, nominal sampling rate (f) 250 Hz (f = 5B) temperature operating range 34-41 &#176;C warranted battery life 1.5 months</td>
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automatic detection of highly organized theta oscillations in the murine eeg

西塔活性在septohippocampal系统中产生，并且可以使用深海马电极和植入脑电图（EEG）无线电遥测或系绳系统的方法进行记录。药理学上，海马THETA是多相（见二元理论），并且可以分化为I型和II型2θ。这些个别脑电图亚型都与特定的认知和行为状态，如觉醒，勘探，学习和记忆，更高的综合功能，等等。在神经变性疾病如阿尔茨海默氏症，结构和septohippocampal系统的功能的改变可导致受损THETA活性/振荡。海马脑电图的标准定量分析包括快速傅里叶变换（FFT）为基础的时频分析。但是，此过程不提供有关特别是在一般和高度组织THETA振荡THETA活动的详细信息。为了获得DETA在海马高度组织THETA振荡ILED的信息，我们已经开发了一种新的分析方法。该方法允许高度组织THETA振荡和其频率特性的持续时间的时间和成本有效的量化。

西塔活性可以被记录在一个大范围的中枢神经系统（CNS）区域中。在这里，我们提出从小鼠海马THETA振荡的分析。在不同的行为和认知状态，可能会发生这种振荡。强烈建议来分析自发的长期任务相关的短期和药理学诱导条件下THETA振荡。 图1显示了控制条件下，具有代表性的海马CA1记录。如果动物是不是在一个自发的"THETA国家"海马脑电图的特点往往是大的不规则振幅（LIA）的活动。毒蕈碱受体激动剂（如槟榔碱，毛果芸香碱，或聚氨酯）的结果可以通过阿托品（50毫克/公斤，IP， 图1）被封锁高度组织THETA振荡的管理。 图2）。根据这种分类，能够量化自发条件或特定行为和认知的任务下THETA振荡的总持续时间。 为了分析一个30分钟的脑电图段（如药理氨基甲酸酯/阿托品THETA夹层），我们首先对0.2-12 Hz的频率范围内，其中显示幅度（毫伏）在一个color-执行的时间 - 频率分析编码方式（ 图3 A）。作为成为在图3A显而易见，高幅THETA活性，这是通过脑电图（白色箭头）的目视检查确认，伴随着增量的频率范围内的低幅度。然后，的最大振幅THETA（3.5-8.5赫兹）和增量（2-3.4赫兹）的频率范围绘制（ 图3 B）。系统的相关性的研究显示，最大THETA振幅最大增量幅度超过1.5，比值指示高度组织THETA振荡（ 图3℃）。 图4展示了聚氨酯如何诱导海马THETA振荡（白圈图4 II）。聚氨酯是多目标药物可以触发由于对毒蕈碱受体的激动作用II型2θ。继阿托品注射液（ 图4 III），这些II型THETA振荡（阿托品敏感THETA振荡）废除。考虑到，毒蕈碱受体激动剂，除阿托品，具有影响THETA发生和θ封锁的时间特性个体药代动力学性质是重要的。应当指出的是阿托品不敏感的I型THETA保持unaff通过毒蕈碱受体拮抗剂ected。 整个THETA检测和定量的工具的概要如图5所示。它导致在振幅，频率，和总和的计算/平均THETA持续时间。相反先前描述的技术，它利用具有高精度的基于小波的方法。这里所描述的分析用具具有应用程序的多个领域。西塔振荡在septohippocampal系统产生，并且通常由神经变性过程， 例如，在阿尔茨海默病损害。阿尔茨海默氏病的众多的小鼠模型已被描述，在同源性，同构，和可预测性而有所不同。这些模型的报告显示出在THETA活性降低，而其他被示出，以显示在THETA活性的增加，为此的原因仍有待确定。我们成功地运用了θ检测ŤOOL这里描述阿尔茨海默病8的5XFAD模型来表征改变THETA振荡结构。但是，它也可能在癫痫研究和神经精神性疾病的应用。 <img alt="图1" src="/files/ftp_upload/55089/55089fig1.jpg" /> 图1: 西塔振动在C57BL / 6小鼠。自发的条件（Ⅰ）和下列氨基甲酸酯注射下无线电遥测海马CA1区记录（800毫克/千克，IP，二）。以下氨基甲酸酯注射，高度组织THETA振荡变得可见，这可以通过阿托品（50毫克/千克，IP）被阻止。这个数字已经从20参考修改许可。 <a href="http://ecsource.jove.com/files/ftp_upload/55089/55089fig1large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> 图 2: 深CA1脑电图记录从C57BL / 6小鼠一种基于小波变换分析。 （A和B）两2.5 - S的脑电图历元被描绘，在视觉上归类为分别非-θ和θ段。 （C和D）在0.2-12赫兹的范围显示在A和B的CA1脑电图段，振幅为颜色编码的时频分析。在C时频分析显示出关于频率和时间不规则，波动THETA架构，而具有高度同步THETA振荡一个段的特征在于6 Hz的几乎恒定的频率的规则的，非脉动的高振幅2θ。最大THETA最大增量振幅的比率是在C 1.25和D中4.67，明确地分类<st荣&gt; B，为THETA振荡EEG段。这个数字是从20引用转载，许可。 <a href="http://ecsource.jove.com/files/ftp_upload/55089/55089fig2large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图3" src="/files/ftp_upload/55089/55089fig3.jpg" /> 图3:一种基于小波变换的Theta检测工具。 （A）一种30分钟的脑电图段的时频分析（未示出）已记录下列氨基甲酸酯施用。在0.2-12赫兹的范围内进行的复杂的基于小波的Morlet分析，具有幅度（毫伏）是颜色编码。 （ 二 ）该图像显示的θ频带（3.5-8.5赫兹，绿色）和30分钟的脑电图段的上三角带（2-3.4赫兹，红色）的最大振幅。 （C）该图显示的最大THETA振幅的比（绿色在B）和最大增量幅度（红色中的B）。需要注意的是高度同步的振荡THETA关联与C.阈上比这个数字是从20引用转载，许可。 <a href="http://ecsource.jove.com/files/ftp_upload/55089/55089fig3large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图4" src="/files/ftp_upload/55089/55089fig4.jpg" /> 图4: 在药理学诱导，高度组织化的Theta振荡的基于小波的分析。代表30分钟的脑电图段（未示出）在0-12赫兹的与振幅（毫伏）作为颜色编码的频率范围进行了分析。一种聚氨酯注射800毫克/公斤，IP，导致高度组织THETA振荡的零散发生，大约有6赫兹（白圈）的主要频率。继在一个注射阿托品在50毫克/公斤，IP，这些THETA振荡取消。这个数字是从20引用转载，许可。 <a href="http://ecsource.jove.com/files/ftp_upload/55089/55089fig4large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图5" src="/files/ftp_upload/55089/55089fig5.jpg" /> 图5: 流程图，说明高度组织化的Theta振荡从小鼠CA1录制的量化 。 II型THETA振荡可以使用控制的记录（相位），后喷射（ 例如，氨基甲酸乙酯，槟榔碱，毛果芸香碱或）相，和一个后阿托品相（A1）进行分析。从各相30分钟的脑电图段（A2），是时间-频率使用基于小波的方法（B1和B2）从0.2-12赫兹的范围内进行分析。接下来，THETASeğmen市吨检测初始化（C1），从而在THETA范围的时间-频率特性（3.5-8.5赫兹，C2）和用于脑电图历元的上三角范围（2-3.4赫兹，C3）是2.5秒每细看（C4和C5）。接着，将振幅分析过的θ和增量的频率范围内描绘的最大值（C6和C7）。如果THETA /增量的最大振幅超过1.5，在2.5秒的EEG段分类为高度组织THETA振荡（C8）的时代，具有限定的幅度和频率（D1-D3）。这THETA检测工具允许THETA振荡架构（E1）的量化。 <a href="http://ecsource.jove.com/files/ftp_upload/55089/55089fig5large.jpg" target="_blank">请点击此处查看该图的放大版本。</a>

Watch this Scientific Journal Video about Automatic Detection of Highly Organized Theta Oscillations in the Murine EEG at JoVE.com

Automatic Detection of Highly Organized Theta Oscillations in the Murine EEG

Theta activity in the hippocampus is related to specific cognitive and behavioral stages. Here, we describe an analytical method to detect highly-organized theta oscillations within the hippocampus using a time-frequency (i.e., wavelet analysis)-based approach.

高度组织的Theta振荡在鼠脑的自动检测

Theta activity is generated in the septohippocampal system and can be recorded using deep intrahippocampal electrodes and implantable ...

automatic-detection-highly-organized-theta-oscillations-murine

Nanyang Technological University

Research

JoVE Journal

Behavior

9.1K 次观看.  University of Cologne. Theta activity in the hippocampus is related to specific cognitive and behavioral stages. Here, we describe an analytical method to detect highly-organized theta oscillations within the hippocampus using a time-frequency (i.e., wavelet analysis)-based approach.

视频: Automatic Detection of Highly Organized Theta Oscillations in the Murine EEG

Best Current Practice for Obtaining High Quality EEG Data During Simultaneous fMRI

Simultaneous EEG-fMRI allows the excellent temporal resolution of EEG to be combined with the high spatial accuracy of fMRI. The data from these two modalities can be combined in a number of ways, but all rely on the acquisition of high quality EEG and fMRI data. EEG data acquired during simultaneous fMRI are affected by several artifacts, including the gradient artefact (due to the changing magnetic field gradients required for fMRI), the pulse artefact (linked to the cardiac cycle) and movement artifacts (resulting from movements in the strong magnetic field of the scanner, and muscle activity). Post-processing methods for successfully correcting the gradient and pulse artifacts require a number of criteria to be satisfied during data acquisition. Minimizing head motion during EEG-fMRI is also imperative for limiting the generation of artifacts.
Interactions between the radio frequency (RF) pulses required for MRI and the EEG hardware may occur and can cause heating. This is only a significant risk if safety guidelines are not satisfied. Hardware design and set-up, as well as careful selection of which MR sequences are run with the EEG hardware present must therefore be considered.
The above issues highlight the importance of the choice of the experimental protocol employed when performing a simultaneous EEG-fMRI experiment. Based on previous research we describe an optimal experimental set-up. This provides high quality EEG data during simultaneous fMRI when using commercial EEG and fMRI systems, with safety risks to the subject minimized. We demonstrate this set-up in an EEG-fMRI experiment using a simple visual stimulus. However, much more complex stimuli can be used. Here we show the EEG-fMRI set-up using a Brain Products GmbH (Gilching, Germany) MRplus, 32 channel EEG system in conjunction with a Philips Achieva (Best, Netherlands) 3T MR scanner, although many of the techniques are transferable to other systems.

Simultaneous electroencephalography (EEG) and functional Magnetic Resonance imaging (fMRI) is a powerful neuroimaging tool. However, the inside of an MRI scanner forms a difficult environment for EEG data recording and safety must be considered whenever operating EEG equipment inside a scanner. Here, we present an optimised EEG-fMRI data acquisition protocol.

获得高质量的脑电数据在同步功能磁共振成像的当前最佳实践

Simultaneous  EEG-fMRI allows the excellent temporal resolution of EEG to be combined with the  high spatial accuracy of fMRI. The data  from these two ...

科研

行为学

Simultaneous EEG Monitoring During Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a technique that delivers weak electric currents through the scalp. This constant electric current induces shifts in neuronal membrane excitability, resulting in secondary changes in cortical activity. Although tDCS has most of its neuromodulatory effects on the underlying cortex, tDCS effects can also be observed in distant neural networks. Therefore, concomitant EEG monitoring of the effects of tDCS can provide valuable information on the mechanisms of tDCS. In addition, EEG findings can be an important surrogate marker for the effects of tDCS and thus can be used to optimize its parameters. This combined EEG-tDCS system can also be used for preventive treatment of neurological conditions characterized by abnormal peaks of cortical excitability, such as seizures. Such a system would be the basis of a non-invasive closed-loop device. In this article, we present a novel device that is capable of utilizing tDCS and EEG simultaneously. For that, we describe in a step-by-step fashion the main procedures of the application of this device using schematic figures, tables and video demonstrations. Additionally, we provide a literature review on clinical uses of tDCS and its cortical effects measured by EEG techniques.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has shown initial therapeutic effects in several neurological conditions. The main mechanism underlying these therapeutic effects is the modulation of cortical excitability. Therefore, online monitoring of cortical excitability would help guide stimulation parameters and optimize its therapeutic effects. In the present article we review the use of a novel device that combines simultaneous tDCS and EEG monitoring in real time.

同时脑电图监测在经颅直流电刺激

Transcranial  direct current stimulation (tDCS) is a technique that delivers weak electric  currents through the scalp. This constant electric current ...

Behavioral Phenotyping of Murine Disease Models with the Integrated Behavioral Station (INBEST)

Due to rapid advances in genetic engineering, small rodents have become the preferred subjects in many disciplines of biomedical research. In studies of chronic CNS disorders, there is an increasing demand for murine models with high validity at the behavioral level. However, multiple pathogenic mechanisms and complex functional deficits often impose challenges to reliably measure and interpret behavior of chronically sick mice. Therefore, the assessment of peripheral pathology and a behavioral profile at several time points using a battery of tests are required. Video-tracking, behavioral spectroscopy, and remote acquisition of physiological measures are emerging technologies that allow for comprehensive, accurate, and unbiased behavioral analysis in a home-base-like setting. This report describes a refined phenotyping protocol, which includes a custom-made monitoring apparatus (Integrated Behavioral Station, INBEST) that focuses on prolonged measurements of basic functional outputs, such as spontaneous activity, food/water intake and motivated behavior in a relatively stress-free environment. Technical and conceptual improvements in INBEST design may further promote reproducibility and standardization of behavioral studies.

Behavioral Phenotyping of Murine Disease Models with the Integrated Behavioral Station INBEST

Prolonged and comprehensive monitoring of mice in a home-cage environment provides a deeper understanding of aberrant behavior in murine models of brain diseases. This paper describes the Integrated Behavioral Station (INBEST) as the key component of contemporary behavioral analysis.

小鼠疾病模型的集成行为车站行为表型（INBEST）

Due to rapid advances in genetic engineering, small rodents have become the preferred subjects in many disciplines of biomedical research. In studies of ...

Cortical Source Analysis of High-Density EEG Recordings in Children

EEG is traditionally described as a neuroimaging technique with high temporal and low spatial resolution. Recent advances in biophysical modelling and signal processing make it possible to exploit information from other imaging modalities like structural MRI that provide high spatial resolution to overcome this constraint1. This is especially useful for investigations that require high resolution in the temporal as well as spatial domain. In addition, due to the easy application and low cost of EEG recordings, EEG is often the method of choice when working with populations, such as young children, that do not tolerate functional MRI scans well. However, in order to investigate which neural substrates are involved, anatomical information from structural MRI is still needed. Most EEG analysis packages work with standard head models that are based on adult anatomy. The accuracy of these models when used for children is limited2, because the composition and spatial configuration of head tissues changes dramatically over development3.&#160;
In the present paper, we provide an overview of our recent work in utilizing head models based on individual structural MRI scans or age specific head models to reconstruct the cortical generators of high density EEG. This article describes how&#160;EEG recordings are acquired, processed, and analyzed with pediatric populations at the London Baby Lab, including laboratory setup, task design, EEG preprocessing, MRI processing, and EEG channel level and source analysis.&#160;

In recent years, there has been increasing interest in estimating the cortical sources of scalp measured electrical activity for cognitive neuroscience experiments. This article describes how high density EEG is acquired and how recordings are processed for cortical source estimation in children from the age of 2 years at the London Baby Lab.

高密度的脑电图记录在儿童的皮质来源分析

EEG is traditionally described as a neuroimaging technique with high temporal and low spatial resolution. Recent advances in biophysical modelling and ...

Infant Auditory Processing and Event-related Brain Oscillations

Rapid auditory processing and acoustic change detection abilities play a critical role in allowing human infants to efficiently process the fine spectral and temporal changes that are characteristic of human language. These abilities lay the foundation for effective language acquisition; allowing infants to hone in on the sounds of their native language. Invasive procedures in animals and scalp-recorded potentials from human adults suggest that simultaneous, rhythmic activity (oscillations) between and within brain regions are fundamental to sensory development; determining the resolution with which incoming stimuli are parsed. At this time, little is known about oscillatory dynamics in human infant development. However, animal neurophysiology and adult EEG data provide the basis for a strong hypothesis that rapid auditory processing in infants is mediated by oscillatory synchrony in discrete frequency bands. In order to investigate this, 128-channel, high-density EEG responses of 4-month old infants to frequency change in tone pairs, presented in two rate conditions (Rapid: 70 msec ISI and Control: 300 msec ISI) were examined. To determine the frequency band and magnitude of activity, auditory evoked response averages were first co-registered with age-appropriate brain templates. Next, the principal components of the response were identified and localized using a two-dipole model of brain activity. Single-trial analysis of oscillatory power showed a robust index of frequency change processing in bursts of Theta band (3 - 8 Hz) activity in both right and left auditory cortices, with left activation more prominent in the Rapid condition. These methods have produced data that are not only some of the first reported evoked oscillations analyses in infants, but are also, importantly, the product of a well-established method of recording and analyzing clean, meticulously collected, infant EEG and ERPs. In this article, we describe our method for infant EEG net application, recording, dynamic brain response analysis, and representative results.

High-density electroencephalography (dEEG) is being used increasingly to study brain development and plasticity in the early years of life. Here we present an application of sophisticated analysis techniques that builds on traditional EEG recording to understand the oscillatory dynamics of rapid auditory processing in the infant brain.

婴儿听觉处理和事件相关的脑振荡

Rapid auditory processing and acoustic change detection abilities play a critical role in allowing human infants to efficiently process the fine spectral ...

Measurement of Vibration Detection Threshold and Tactile Spatial Acuity in Human Subjects

Tests that allow the precise determination of psychophysical thresholds for vibration and grating orientation provide valuable information about mechanosensory function that are relevant for clinical diagnosis as well as for basic research. Here, we describe two psychophysical tests designed to determine the vibration detection threshold (automated system) and tactile spatial acuity (handheld device). Both procedures implement a two-interval forced-choice and a transformed-rule up and down experimental paradigm. These tests have been used to obtain mechanosensory profiles for individuals from distinct human cohorts such as twins or people with sensorineural deafness.

Here, we present protocols to determine vibration detection thresholds and tactile acuity using psychophysical methods in man.

振动检测阈值和触觉敏锐的空间在人类受试者的测量

Tests that allow the precise determination of psychophysical thresholds for vibration and grating orientation provide valuable information about ...

The Social Dimension of Stress: Experimental Manipulations of Social Support and Social Identity in the Trier Social Stress Test

In many situations humans are influenced by the behavior of other people and their relationships with them. For example, in stressful situations supportive behavior of other people as well as positive social relationships can act as powerful resources to cope with stress. In order to study the interplay between these variables, this protocol describes two effective experimental manipulations of social relationships and supportive behavior in the laboratory. In the present article, these two manipulations are implemented in the Trier Social Stress Test (TSST)&#8212;a standard stress induction paradigm in which participants are subjected to a simulated job interview. More precisely, we propose (a) a manipulation of the relationship between different protagonists in the TSST by making a shared social identity salient and (b) a manipulation of the behavior of the TSST-selection committee, which acts either supportively or unsupportively. These two experimental manipulations are designed in a modular fashion and can be applied independently of each other but can also be combined. Moreover, these two manipulations can also be integrated into other stress protocols and into other standardized social interactions such as trust games, negotiation tasks, or other group tasks.

Previous research on the social dimension of stress has focused on two important variables: social identity and social support. This protocol introduces an effective experimental manipulation of these two social variables and describes their implementation in a standard stress induction paradigm (Trier Social Stress Test).

应力的社会问题:社会支持和社会认同的特里尔社会的实验操作压力测试

In many situations humans are influenced by the behavior of other people and their relationships with them. For example, in stressful situations ...

The Treadmill Fatigue Test: A Simple, High-throughput Assay of Fatigue-like Behavior for the Mouse

Fatigue is a prominent symptom in many diseases and disorders and reduces quality of life for many people. The lack of clear pathogenesis and failure of current interventions to adequately treat fatigue in all patients leaves a need for new treatment options. Despite the therapeutic need and importance of preclinical research in helping identify promising novel treatments, few preclinical assays of fatigue are available. Moreover, the most common preclinical assay used to assess fatigue-like behavior, voluntary wheel running, is not suitable for use with some strains of mice, may not be sensitive to drugs that reduce fatigue, and has relatively low throughput. The current protocol describes a novel, non-voluntary preclinical assay of fatigue-like behavior, the treadmill fatigue test, and provides evidence of its efficacy in detecting fatigue-like behavior in mice treated with a chemotherapy drug known to cause fatigue in humans and fatigue-like behavior in animals. This assay may be a beneficial alternative to wheel running, as fatigue-like behavior and potential interventions can be assessed in a greater number of mice over a shorter time frame, thus permitting faster discovery of new therapeutic options.

Fatigue is a common, undertreated and frequently poorly-understood symptom in many diseases and disorders. New preclinical assays of fatigue may help to improve current understanding and future treatment of fatigue. To that end, the current protocol provides a novel means of measuring fatigue-like behavior in the mouse.

跑步机疲劳试验:疲劳类似的行为，为鼠标操作简单，高通量检测

Fatigue is a prominent symptom in many diseases and disorders and reduces quality of life for many people. The lack of clear pathogenesis and failure of ...

A Within-subjects Experimental Protocol to Assess the Effects of Social Input on Infant EEG

Despite the importance of social interactions for infant brain development, little research has assessed functional neural activation while infants socially interact. Electroencephalography (EEG) power is an advantageous technique to assess infant functional neural activation. However, many studies record infant EEG only during one baseline condition. This protocol describes a paradigm that is designed to comprehensively assess infant EEG activity in both social and nonsocial contexts as well as tease apart how different types of social inputs differentially relate to infant EEG. The within-subjects paradigm includes four controlled conditions. In the nonsocial condition, infants view objects on computer screens. The joint attention condition involves an experimenter directing the infant's attention to pictures. The joint attention condition includes three types of social input: language, face-to-face interaction, and the presence of joint attention. Differences in infant EEG between the nonsocial and joint attention conditions could be due to any of these three types of input. Therefore, two additional conditions (one with language input while the experimenter is hidden behind a screen and one with face-to-face interaction) were included to assess the driving contextual factors in patterns of infant neural activation. Representative results demonstrate that infant EEG power varied by condition, both overall and differentially by brain region, supporting the functional nature of infant EEG power. This technique is advantageous in that it includes conditions that are clearly social or nonsocial and allows for examination of how specific types of social input relate to EEG power. This paradigm can be used to assess how individual differences in age, affect, socioeconomic status, and parent-infant interaction quality relate to the development of the social brain. Based on the demonstrated functional nature of infant EEG power, future studies should consider the role of EEG recording context and design conditions that are clearly social or nonsocial.

This novel protocol is designed to assess the neural bases of social interaction in infants. The paradigm is designed to tease apart how various social inputs such as language, joint attention, and face-to-face interaction relate to infant neural activation. Infant EEG power is recorded during both social and nonsocial conditions.

一个被试内实验协议，以评估对婴幼儿脑社会投入的影响

Despite the importance of social interactions for infant brain development, little research has assessed functional neural activation while infants ...

Continuous Theta Burst Stimulation of the Posterior Medial Frontal Cortex to Experimentally Reduce Ideological Threat Responses

Decades of behavioral science research have documented functional shifts in attitudes and ideological adherence in response to various challenges, but little work to date has illuminated the neural mechanisms underlying these dynamics. This paper describes how continuous theta burst transcranial magnetic stimulation may be employed to experimentally assess the causal contribution of cortical regions to threat-related ideological shifts. In the example protocol provided here, participants are exposed to a threat prime-an explicit reminder of their own inevitable death and bodily decomposition-following a downregulation of the posterior medial frontal cortex (pMFC) or a sham stimulation. Next, disguised within a series of distracter tasks, participants' relative degree of ideological adherence is assessed-in the present example, with regard to coalitional prejudice and religious belief. Participants for whom the pMFC has been downregulated exhibit less coalitionally biased responses to an immigrant critical of the participants' national in-group, and less conviction in positive afterlife beliefs (i.e., God, angels, and heaven), despite having recently been reminded of death. These results complement prior findings that continuous theta burst stimulation of the pMFC influences social conformity and sharing and illustrate the feasibility of investigating the neural basis of high-level social cognitive shifts using transcranial magnetic stimulation.

Threats reliably evoke shifts in high-level ideological investment, but little work to date has explored the neural mechanisms underlying these dynamics. This paper describes how continuous theta burst transcranial magnetic stimulation may be employed to test the contribution of the posterior medial frontal cortex (and/or other regions) to threat-related ideological shifts.

连续θ爆刺激后内侧额叶皮层实验降低意识形态威胁反应

Decades of behavioral science research have documented functional shifts in attitudes and ideological adherence in response to various challenges, but ...