这种方法是利用从威康信托基金会，医学研究理事会，美国国家卫生研究院牛津大学生物医学研究中心，以及Rosetrees信托资金开发的。功能性神经外科UCL单位是由英国帕金森呼吁和纪念碑信任支持。

1，同意和生物标记物鉴定 该协议已审阅及批准由国家研究伦理委员会服务南环-牛津A。 <ol><li>确定适当的科目的学习：对象是那些谁是临床上确定为适用于深部脑刺激（药物难治性帕金森氏病）。注：电极植入（1天）后进行实验前和电池/刺激器的位置（7天），而导线外部化。 </li><li>同意对患者刺激试验和过夜帕金森停药。 </li><li>下面帕金森用药12小时撤出，连接外部化DBS电极，以合适的放大器（放大器必须设计，安全测试和验证用于人体颅内神经生理用）16。 </li><li>记录局部场电位（LFP）休息时从BIL所有联系人aterally（负0-3＆R 0-3）。 </li><li>通过录音与相邻接触的减法创建双极蒙太奇（0,2和1,3）。 </li><li>进行功率谱分析，以确定患者的具体测试峰值频率和双极性接触对具有最高的β振幅刺激测试。注：大多数帕金森患者断药有一个测试峰值2。如果没有测试峰值是明显的断药，患者应排除进一步分析，因为这可能代表星展银行针对并发症。 </li><li>选择接触为与测试最高幅度桥双极性接触对（0,2或1,3）单极刺激。 </li></ol> 2，连接病人来ADBS设置<ol><li>星展电极连接到模拟放大器和滤波器。注：3间带通滤波器 - 37赫兹，其中x 9,100增益。 </li><li>连接参考耐心。注：参考应为5厘米斯坦连接×5厘米的神经刺激凝胶电极片DARD2毫米单极电极丝。将电极在左锁骨。 </li><li>模拟放大器连接到A / D转换器和便携式电脑的运行信号分析软件。第二阶段进行数字过滤围绕患者特定的β峰的信号与4赫兹通带。监测β-振幅，并使用它来控制刺激与预先设定的阈值。光滑的β幅度与平滑窗口（400毫秒是试探性地有效在此设置。） </li><li>连接的D / A触发刺激。 </li><li>刺激器连接到病人通过放大器。注意：为了安全，确保电荷密度被限制在&lt;30μQ/厘米2和刺激器具有线性输入-输出功能。光学隔离所有连接到病人。刺激器的设计应与EN60601-1医疗安全标准作为参考进行测试。 </li></ol>传统的连续刺激3。测试<ol><li>打开以往的高频增产化，但最初在零电压（100毫秒，130赫兹，0 V）。在接触双极接触对具有最高的β幅度桥接应用单极刺激。连续监测刺激读出整个实验，以确保交付的刺激与预期相符。 </li><li>慢慢增加刺激电压0.5 V增量每隔几分钟，寻找临床效应阈值。建立临床上有用的刺激电压（一般为1.5〜3.0 V）伴随着很少或没有副作用，如感觉异常。 </li></ol> 4，阈值与ON / OFF开关和触发器的测试设置<ol><li>随着刺激在临床上有效电压，以250毫秒斜坡向下切换刺激器关闭。 </li><li>随着刺激在临床上有效电压，开关与​​250毫秒升温了刺激。 </li><li>查询有关感觉异常以及任何其他可能的副作用在经历刺激的切换和关闭。&lt;/ LI&gt; <li>如果副作用都存在，由0.25 V降低电压，并重复步骤4.1至4.3，直到下面的感觉异常时开/关切换的阈值。 </li><li>通过滴定发现与开/关再次切换为感觉异常的阈值和设定的电压的正下方（0.1 V）这个阈值进行进一步的测试。如果这在临床上是无效的，然后尝试其他的联系（联系人中选择1或2）。注：在交换刺激和关闭也可以在一些患者中引起尖峰的工件，可能与电容在组织电极界面充电。由于信号是通带滤波在公测带，设置触发电平之前，这件神器被大大衰减。然而，在一些情况下，这种伪影是足以引起自触发。为了解决这个问题在这些情况下，我们减少刺激的电压，并且增加了触发阈逃脱自触发。 ，这可能是解决今后如果有必要另一种方式是通过掺入一个锁定期内的每个触发后发病，以避免自触发。 </li><li>打开刺激在电压只是根据上述所确定的开/关切换的感觉异常的阈值。 </li><li>增加的β振幅触发阈值的水平，导致在最小的时间上的刺激，同时保持临床效果。务求在时间上减少刺激至少50％。 </li><li>关闭刺激和离开患者无刺激（以下设置和测试块之间）为10分钟至洗出刺激效应。 </li></ol> 5，测试病人的跨不同的刺激条件<ol><li>保证患者致盲试验条件（自适应星展，传统和关闭）。 </li><li>适用于每个测试条件至少有5分钟的稳定期与运行条件的临床试验开始之前。跨学科平衡测试条件的顺序。固定的电压，脉冲宽度和刺激频率鉴定横跨测试条件新增Cally以便唯一的区别涉及刺激的时机相对于β-振幅。 </li><li>在预定的固定点开始刺激后（ 例如 ，作为最低300秒），评估通过UPDRS量表评定患者的临床效果。 </li><li>视频记录评估，然后盲速率由独立的专家离线（不包括刚性。） </li><li>用客观指标（加速度计或活动记录仪）进行临床评估。 </li></ol>

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LZ，MH：咨询，差旅支持，演讲费，美敦力，圣裘德。 TF：咨询，AbbVie制药公司，圣犹达，美敦力; PL：咨询，演讲费，美敦力，圣裘德。 PB：咨询公司，美敦力，智人。

本文概述了自适应深部脑刺激在手术后病人的研究和验证的新方法。 DBS治疗的标准治疗帕金森病，特发性震颤和肌张力障碍的一部分，并正在引进并在一定范围内的其他条件，包括丛集性头痛，癫痫，抽动秽语综合症，强迫症和抑郁症测试。目前，所有的临床刺激范式采用连续，开环的刺激，尽管这些简单的刺激范式往往是有效的，希望他们能够显著，使它们响应相应疾病的生物标志物，从而优化刺激知情，提高了病人的具体方式。的方法，这里列出，让ADBS患者首次手术（植入电极），前内部化和电池和刺激器植入后外部化的测试。用这种方法，人们希望有前，研究人员可以利用调查的范围为整个星展是用于疾病的生物标志物谱的ADBS的疗效。那么这可能导致在长期植入临床试验。 我们已经使用并发现是成功的协议上面概述。我们为了实现成功的ADBS看出端倪了一些微调的过程中的关键步骤。可在此简单ADBS设置控制参数包括电压，触发阈值，刺激触点和斜坡的持续时间。这些都必须对开关的刺激和关闭（感觉异常）的副作用平衡，技术问题（经常&#39;自我&#39;触发）和临床疗效。切换刺激和关闭会导致在LFP随​​电压变化的工件，尽管滤波，可以潜在地泄漏到感兴趣的频率范围。如果这是严重的，它可以使系统的自触发，即使在不存在的海拔在生物标志物的信号， - 在这里的局部场电位测试活动。这并不代表，因为它有效地导致了ADBS即在所有的时间，因此，模仿其已知是安全CDBS一个安全问题。然而，它导致缺乏反应性的β振幅及以上CDBS因此ADBS的任何潜在的益处的丧失。我们发现，如果需要的话，可避免通过降低刺激电压，提高阈值或改变刺激的触点自触发。刺激的打开和关闭被发现是关于防止皮肤感觉异常，同时保持ADBS的响应性良好的折衷的250毫秒的斜坡。目前参数必须以实现个别患者最好的回应档试探性调整，我们还没有发现一致的规则，适用于集团层面，以可靠地实现这一目标。然而，在迄今研究的所有患者中，我们发现该启发式调整电压，触发阈值和刺激接触激活有效ADBS，和最佳参数，在不到30分钟鉴定。希望的副作用（从开/关切换感觉异常）和工件的污染（可能与组织电极电容）的管理可以进一步调查，并更好地理解推导出有关其最小化更一般化的规则。 勘探潜力参数空间也将变大，并作为生物标志物和刺激增长的算法的复杂性更为复杂。例如，高频功率比，相位幅度耦合和β的变化都被证明与帕金森状态9,10,12,17。本文介绍的方法应该使这些参数及其对刺激他们除了副作用的临床疗效影响的系统调查。然而，经thorough在未来的所有参数的优化很可能是促成一次DBS模型和算法的优化例程集中于生物标志物的反应，而不是临床效果允许参数的限制范围，以凭经验搜索。 这种方法已经证明改进的功耗和临床疗效相比，传统的DBS和必须进一步在PD与进步在我们的关于生物标志物和刺激构图理解改进的潜力。在星展银行被使用，更不用说是已知的有关病理生理学，因此相应的生物标志物尚未完全确定的其他条件。显著需要进一步研究，以充分利用ADBS在帕金森的潜力，并探讨在其他一些潜在的神经和精神症状，其中严重程度及减值波动，随着时间的推移其可行性。

帕金森氏症是一种常见的严重致残退行性运动紊乱，以致长期药物治疗不理想1。星展银行是有效的先进药物难治性帕金森病，但在疗效，副作用方面的限制和成本2。传统的刺激设置启发式由运动障碍专家，留到下一次诊没有改变连续运行。典型刺激参数是60毫秒的脉冲宽度，3 V强度，和130 Hz重复。然而，这种持续的高电压刺激可能会干扰正常的运动功能3。就像心脏起搏成功地从简单的开环系统过渡到复杂响应的闭环系统，在结果相关联的改进，就是希望星展银行同样可以通过使其顺应底层大脑节律改善-自适应星展银行（ADBS）4 ，5。 在奥德呃实现ADBS，它是首先重要的是确定疾病的可靠的生物标记物。帕金森氏病的特征是突出的β-（13-33赫兹）振动记录整个基底节环路2。这些测试振动是由左旋多巴和星展银行的比例提高临床状态6,7抑制。它们是稳定的和在长期健壮，并且可以从用于临床DBS使它们成为生物标志物8有吸引力的目标相同的电极来记录。除了​​β-振荡，一系列的其他更复杂的潜在生物标志物已经确定，已显示出与症状2,9-12严重性。 ADBS原理的证明已经被证明在一个非- PD 13的人类灵长类动物模型。这用一个单一的皮质运动神经元控制的刺激与神经元触发DBS刺激一个固定的延时后发射。该研究报告指出，适应香港专业教育学院的刺激是比传统的星展银行更有效。最近的工作，因为成功推广ADBS给人类，为此提出了这个朱庇特的第14条中的方法。本研究旨在探讨PD患者在不久的术后期前的自己内在的电线和连接它们的电池组/刺激器。贝塔振荡进行实时监控网络和用于控制的高频刺激的时机。这导致了一个降低耗电量&gt; 50％，而运动功能障碍有25％的改善比标准刺激。这些结果将需要在长期植入状态下阈值和有效的刺激参数可以改变，以及药物浓度被复制。因此，生物标志物和控制算法可能需要进行调整和匹配相应地，实际上很可能需要进一步的复杂性，以适应这种不同参数的风景。 ，配备较长期的ST器件imulation和记录目前正在开发和造模在研究设置15。同时有必要建立一个平台，使自适应DBS和算法对支撑其业绩可能带来的好处还有待进一步评估和完善。这是一个重要的步骤，因为误差和次优方法是更难以扭转，一旦系统被内化于长期使用。此外，急性研究是必要的激励克服隐含在发展为慢性内化自适应星展银行体系所面临的挑战的努力。 这个方法报告的目的是使研究人员能够探索各种不同的生物标志物和刺激范式DBS患者和优化参数，以最大限度地提高疗效和减少副作用/功耗。它是同类产品中第一种方法可有效地治疗帕金森，但相对简单，易于应用。该方法被设计吨Ø调查任何DBS病人对他们来说，有一个已知的磷酸锂铁的生物标志物，谁拥有一个时期外化的手术后（当电极导线颅外，并用于实验之前，电池/刺激器插入长达1周的时间）。

<table border="0" cellpadding="0" cellspacing="0" width="573">
	<colgroup>
		<col />
		<col />
		<col />
		<col />
	</colgroup>
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">StimRecord Amplifier (3-37 Hz)</td>
			<td style="width:71px;">In house</td>
			<td style="width:119px;">NA</td>
			<td style="width:167px;">Common mode rejection, 3-37Hz (bandpass), x9500 amplifier. See - Eusebio, A et al. Deep brain stimulation can suppress pathological synchronisation in parkinsonian patients. JNNP (5), 569&#8211;573 (2011)</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">1401 Digital acquisition unit</td>
			<td style="width:71px;">CED</td>
			<td style="width:119px;">Micro 1401-3</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Spike 2 software</td>
			<td style="width:71px;">CED</td>
			<td style="width:119px;">NA</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Stimulator</td>
			<td style="width:71px;">In house</td>
			<td style="width:119px;">NA</td>
			<td>Biphase, variable, ramped stimulator. See - Little et al. Adaptive deep brain stimulation in advanced Parkinson&#39;s disease. Annals of Neurology 2013.</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:216px;">Gel electrode reference pad</td>
			<td style="width:71px;">Axelgaard</td>
			<td style="width:119px;">895220</td>
			<td>5x5 cm PALS platinum gel electrode pad</td>
		</tr>
	</tbody>
</table>

controlling parkinson's disease with adaptive deep brain stimulation

自适应深部脑刺激（ADBS）具有改善帕金森氏病的通过根据脉动疾病和药物状态优化刺激实时治疗的潜力。在自适应星展目前的实现我们记录并植入患者的帕金森氏症的早期手术后期间丘脑底核的DBS电极刺激。局部场电位类似物被传递到数据采集单元在那里它们被数字化再过滤围绕患者特定的β峰，整流，平滑，得到的β振幅的在线阅读之前过滤3和47赫兹之间。乙型振幅的阈值被设定试探，而如果划线，通过一个触发信号给激励器。然后，刺激器刺激爬升到一个预先确定的临床上有效的电压超过250毫秒，并继续刺激直到测试振幅再次下落低于阈值。刺激继续以这种方式与倾斜DBS的短暂发作期间提高测试电源的时期。 稳定（5分钟），通过运动功能的非盲和盲法评估视频使用选择的分数从统一的帕金森评定量表（UPDRS）的最低期限后的临床疗效进行评估。最近的工作已经证明在降低功耗与ADBS以及在临床评分的改善相对于传统的DBS。慢性ADBS现在可以在造模帕金森。

使用这种方法的结果最近已被使用该协议的β振幅（ 图1）14公开。这项研究表明，临床上有效的刺激可尽管时间减少&gt; 50％的刺激（P &lt;0.001）来实现。也有人指出，时间上的刺激，尽管趋于一个恒定的触发阈值（双尾，单样本t检验，t 7 = 3.2，P = 0.01）逐渐下降。马达的分数是由66％和50％时在盲和双盲条件ADBS，分别改善。尽管总的刺激量的减少-临床结果为29％（P = 0.03）和27％（P = 0.005），更好的ADBS组与传统星展集团（非盲法分别蒙蔽， 图2）进行比较。 <img alt="图1" fo:content-width="5in" fo:src="/files/ftp_upload/51403/51403fig1highres.jpg"SRC =“/ files/ftp_upload/51403/51403fig1.jpg”/&gt; 图1实验装置实验装置进行适应性脑深部电刺激外部化科目。双极局部场电位（LFP）是通过一个定制的StimRecord放大器，过滤器（3-37赫兹）和放大（X9，100）。的类似物（A）的输出被传递到一个数据采集单元，它转换到所显示的便携式计算机上的一个数字（D）的信号。该信号被周围的β峰数字滤波在实时转换为测试幅度由整流和平滑。的阈值被设置触发刺激时测试功率超过阈值的2双极记录电极之间的单极蒙太奇。刺激终止时，测试电源再次低于阈值。（转载自神经病学纪事许可。） <a href="https://www.jove.com/files/ftp_upload/51403/51403fig1highres.jpg" target="_blank">请点击此处查看LAR</a>GER版本这个数字。 <img alt="图2" fo:content-width="5in" fo:src="/files/ftp_upload/51403/51403fig2highres.jpg" src="/files/ftp_upload/51403/51403fig2.jpg" /> 图2。临床改善。平均在hemibody UPDRS评分±标准差变动百分比（项目20，22，和23）与不同的刺激条件下所蒙蔽专家（B）在实验阶段（A）或从录像评估盲。 Asterixes表示多重比较的错误发现率的过程如下修正显著差异。所有的变化都来自未刺激状态显著，除盲得分随机刺激（转载自神经病学纪事许可。） <a href="https://www.jove.com/files/ftp_upload/51403/51403fig2highres.jpg" target="_blank">请点击此处查看大图</a>这个数字。

Watch this Scientific Journal Video about Controlling Parkinson's Disease With Adaptive Deep Brain Stimulation at JoVE.com

Controlling Parkinson&#039;s Disease With Adaptive Deep Brain Stimulation

自适应深部脑刺激（ADBS）是有效的帕金森氏病，改善症状和降低功耗相比传统的深部脑刺激（CDBS）。在ADBS我们实时跟踪局部场电位的生物标志物（β-振荡幅度），并以此来控制刺激的时机。

控制帕金森氏症与自适应深部脑刺激

Adaptive deep brain stimulation (aDBS) has the potential to improve the treatment of Parkinson&#39;s disease by optimizing stimulation in real time ...

controlling-parkinson-s-disease-with-adaptive-deep-brain-stimulation

Research

JoVE Journal

Medicine

Controlling Parkinson's Disease With Adaptive Deep Brain Stimulation

22.0K 次观看.  University of Oxford. 自适应深部脑刺激（ADBS）是有效的帕金森氏病，改善症状和降低功耗相比传统的深部脑刺激（CDBS）。在ADBS我们实时跟踪局部场电位的生物标志物（β-振荡幅度），并以此来控制刺激的时机。 

视频: Controlling Parkinson's Disease With Adaptive Deep Brain Stimulation

Intra-Operative Behavioral Tasks in Awake Humans Undergoing Deep Brain Stimulation Surgery

Deep brain stimulation (DBS) is a surgical procedure that directs chronic, high frequency electrical stimulation to specific targets in the brain through implanted electrodes. Deep brain stimulation was first implemented as a therapeutic modality by Benabid et al. in the late 1980s, when he used this technique to stimulate the ventral intermediate nucleus of the thalamus for the treatment of tremor 1. Currently, the procedure is used to treat patients who fail to respond adequately to medical management for diseases such as Parkinson's, dystonia, and essential tremor. The efficacy of this procedure for the treatment of Parkinson's disease has been demonstrated in well-powered, randomized controlled trials 2. Presently, the U.S. Food and Drug Administration has approved DBS as a treatment for patients with medically refractory essential tremor, Parkinson's disease, and dystonia. Additionally, DBS is currently being evaluated for the treatment of other psychiatric and neurological disorders, such as obsessive compulsive disorder, major depressive disorder, and epilepsy. 
DBS has not only been shown to help people by improving their quality of life, it also provides researchers with the unique opportunity to study and understand the human brain. Microelectrode recordings are routinely performed during DBS surgery in order to enhance the precision of anatomical targeting. Firing patterns of individual neurons can therefore be recorded while the subject performs a behavioral task. Early studies using these data focused on descriptive aspects, including firing and burst rates, and frequency modulation 3. More recent studies have focused on cognitive aspects of behavior in relation to neuronal activity 4,5. This article will provide a description of the intra-operative methods used to perform behavioral tasks and record neuronal data with awake patients during DBS cases. Our exposition of the process of acquiring electrophysiological data will illuminate the current scope and limitations of intra-operative human experiments.

Deep brain stimulation surgery offers a unique opportunity to examine information encoding in the awake human brain. This article will describe intra-operative methods used to perform cognitive and behavioral tasks while simultaneously acquiring physiological data such as EMG, single-unit neuronal activity and/or local field potentials.

在接受深部脑刺激手术术中唤醒人类行为任务

Deep brain stimulation (DBS) is a surgical procedure that directs chronic, high frequency electrical stimulation to specific targets in the brain through ...

科研

医学

Development of a Unilaterally-lesioned 6-OHDA Mouse Model of Parkinson's Disease

The unilaterally lesioned 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) has proved to be invaluable in advancing our understanding of the mechanisms underlying parkinsonian symptoms, since it recapitulates the changes in basal ganglia circuitry and pharmacology observed in parkinsonian patients1-4. However, the precise cellular and molecular changes occurring at cortico-striatal synapses of the output pathways within the striatum, which is the major input region of the basal ganglia remain elusive, and this is believed to be site where pathological abnormalities underlying parkinsonian symptoms arise3,5.
In PD, understanding the mechanisms underlying changes in basal ganglia circuitry following degeneration of the nigro-striatal pathway has been greatly advanced by the development of bacterial artificial chromosome (BAC) mice over-expressing green fluorescent proteins driven by promoters specific for the two striatal output pathways (direct pathway: eGFP-D1; indirect pathway: eGFP-D2 and eGFP-A2a)8, allowing them to be studied in isolation. For example, recent studies have suggested that there are pathological changes in synaptic plasticity in parkinsonian mice9,10. However, these studies utilised juvenile mice and acute models of parkinsonism. It is unclear whether the changes described in adult rats with stable 6-OHDA lesions also occur in these models. Other groups have attempted to generate a stable unilaterally-lesioned 6-OHDA adult mouse model of PD by lesioning the medial forebrain bundle (MFB), unfortunately, the mortality rate in this study was extremely high, with only 14% surviving the surgery for 21 days or longer11. More recent studies have generated intra-nigral lesions with both a low mortality rate &gt;80% loss of dopaminergic neurons, however expression of L-DOPA induced dyskinesia11,12,13,14 was variable in these studies. Another well established mouse model of PD is the MPTP-lesioned mouse15. Whilst this model has proven useful in the assessment of potential neuroprotective agents16, it is less suitable for understanding mechanisms underlying symptoms of PD, as this model often fails to induce motor deficits, and shows a wide variability in the extent of lesion17, 18.
Here we have developed a stable unilateral 6-OHDA-lesioned mouse model of PD by direct administration of 6-OHDA into the MFB, which consistently causes &gt;95% loss of striatal dopamine (as measured by HPLC), as well as producing the behavioural imbalances observed in the well characterised unilateral 6-OHDA-lesioned rat model of PD. This newly developed mouse model of PD will prove a valuable tool in understanding the mechanisms underlying generation of parkinsonian symptoms.

Development of a Unilaterally-lesioned 6-OHDA Mouse Model of Parkinson&#039;s Disease

A protocol for performing unilateral 6-OHDA lesions of the medial forebrain bundle in mice is described. This method has a low mortality rate (13.3 %) with 89% of the surviving animals showing &#62;95% loss of striatal dopamine and 90.63&#177;-4.02 % ipsiversive rotational bias towards the side of the lesion.

1单侧损毁6  - 羟基多巴胺帕金森病小鼠模型的发展

The unilaterally lesioned 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) has proved to be invaluable in advancing our ...

MALDI Imaging Mass Spectrometry of Neuropeptides in Parkinson's Disease

MALDI imaging mass spectrometry (IMS) is a powerful approach that facilitates the spatial analysis of molecular species in biological tissue samples2 (Fig.1). A 12 &mu;m thin tissue section is covered with a MALDI matrix, which facilitates desorption and ionization of intact peptides and proteins that can be detected with a mass analyzer, typically using a MALDI TOF/TOF mass spectrometer. Generally hundreds of peaks can be assessed in a single rat brain tissue section. In contrast to commonly used imaging techniques, this approach does not require prior knowledge of the molecules of interest and allows for unsupervised and comprehensive analysis of multiple molecular species while maintaining high molecular specificity and sensitivity2. Here we describe a MALDI IMS based approach for elucidating region-specific distribution profiles of neuropeptides in the rat brain of an animal model Parkinson's disease (PD). 
PD is a common neurodegenerative disease with a prevalence of 1% for people over 65 of age3,4. The most common symptomatic treatment is based on dopamine replacement using L-DOPA5. However this is accompanied by severe side effects including involuntary abnormal movements, termed L-DOPA-induced dyskinesias (LID)1,3,6. One of the most prominent molecular change in LID is an upregulation of the opioid precursor prodynorphin mRNA7. The dynorphin peptides modulate neurotransmission in brain areas that are essentially involved in movement control7,8. However, to date the exact opioid peptides that originate from processing of the neuropeptide precursor have not been characterized. Therefore, we utilized MALDI IMS in an animal model of experimental Parkinson's disease and L-DOPA induced dyskinesia. 
MALDI imaging mass spectrometry proved to be particularly advantageous with respect to neuropeptide characterization, since commonly used antibody based approaches targets known peptide sequences and previously observed post-translational modifications. By contrast MALDI IMS can unravel novel peptide processing products and thus reveal new molecular mechanisms of neuropeptide modulation of neuronal transmission. While the absolute amount of neuropeptides cannot be determined by MALDI IMS, the relative abundance of peptide ions can be delineated from the mass spectra, giving insights about changing levels in health and disease. In the examples presented here, the peak intensities of dynorphin B, alpha-neoendorphin and substance P were found to be significantly increased in the dorsolateral, but not the dorsomedial, striatum of animals with severe dyskinesia involving facial, trunk and orolingual muscles (Fig. 5). Furthermore, MALDI IMS revealed a correlation between dyskinesia severity and levels of des-tyrosine alpha-neoendorphin, representing a previously unknown mechanism of functional inactivation of dynorphins in the striatum as the removal of N-terminal tyrosine reduces the dynorphin's opioid-receptor binding capacity9. This is the first study on neuropeptide characterization in LID using MALDI IMS and the results highlight the potential of the technique for application in all fields of biomedical research.

MALDI Imaging Mass Spectrometry of Neuropeptides in Parkinson&#039;s Disease

Dopamine replacement pharmacotherapy using L-DOPA is the most commonly used symptomatic treatment of Parkinson&#x2019;s disease, but is accompanied by side effects including involuntary abnormal movements, termed dyskinesia 1. Here, a protocol for MALDI imaging mass spectrometry is presented that detects changes in rat brain neuropeptide levels related to dyskinesia.

MALDI成像帕金森病的神经肽质谱

MALDI imaging mass spectrometry (IMS) is a powerful approach that facilitates the spatial analysis of molecular species in biological tissue samples2 ...

Skin Punch Biopsy Explant Culture for Derivation of Primary Human Fibroblasts

Tissues and cell lines derived from an individual with disease are ideal sources to study disease-related cellular phenotypes. Patient-derived fibroblasts in this protocol have been successfully used in the derivation of induced pluripotent stem cells to model disease1. Early passages of these fibroblasts can also be used for cell-based functional assays to study specific disease pathways, mechanisms2 and subsequent drug screening approaches. The advantage of the presented protocol over enzymatic procedures are 1) the reproducibility of the technique from small amounts of tissue derived from older patients, e.g. patients affected with Parkinson's disease, 2) the technically simple approach over more challenging methodologies using enzymatic treatments, and 3) the time consideration: this protocol takes 15-20 min and can be performed immediately after biopsy arrival. Enzymatic treatments can take up to 4 hr and have the problems of overdigestion, reduction of cell viability and subsequent attachment of cells when not handled properly. This protocol describes the dissection and preparation of a 4-mm human skin biopsy for derivation of a fibroblast culture and has a very high success rate which is important when dealing with patient-derived tissue samples. In this culture, keratinocytes migrate out of the biopsy tissue within the first week after preparation. Fibroblasts appear 7-10 days after the first outgrowth of keratinocytes. DMEM high glucose media supplemented with 20% FBS favors the growth of fibroblasts over keratinocytes and fibroblasts will overgrow the keratinocytes. After 2 passages keratinocytes have been diluted out resulting in relatively homogenous fibroblast cultures which expresses the fibroblast marker SERPINH1 (HSP-47). Using this approach, 15-20 million fibroblasts can be derived in 4-8 weeks for cell banking. The skin dissection takes about 15-20 min, cells are then monitored once a day under the microscope, and media is changed every 2-3 days after attachment and outgrowth of cells.

The fibroblast explant culture protocol from human skin punch biopsies is a technically robust and simple way to derive skin cells within 4-8 weeks for banking of about 15-20 million cells at a low passage number.

推导人类纤维原细胞的皮肤穿刺活检植文化

Tissues and cell lines derived from an individual with disease are ideal sources to study disease-related cellular phenotypes. Patient-derived fibroblasts ...

Isolation of Soluble and Insoluble PrP Oligomers in the Normal Human Brain

The central event in the pathogenesis of prion diseases involves a conversion of the host-encoded cellular prion protein PrPC into its pathogenic isoform PrPSc 1. PrPC is detergent-soluble and sensitive to proteinase K (PK)-digestion, whereas PrPSc forms detergent-insoluble aggregates and is partially resistant to PK2-6. The conversion of PrPC to PrPSc is known to involve a conformational transition of &alpha;-helical to &beta;-sheet structures of the protein. However, the in vivo pathway is still poorly understood. A tentative endogenous PrPSc, intermediate PrP* or "silent prion", has yet to be identified in the uninfected brain7.
Using a combination of biophysical and biochemical approaches, we identified insoluble PrPC aggregates (designated iPrPC) from uninfected mammalian brains and cultured neuronal cells8, 9. Here, we describe detailed procedures of these methods, including ultracentrifugation in detergent buffer, sucrose step gradient sedimentation, size exclusion chromatography, iPrP enrichment by gene 5 protein (g5p) that specifically bind to structurally altered PrP forms10, and PK-treatment. The combination of these approaches isolates not only insoluble PrPSc and PrPC aggregates but also soluble PrPC oligomers from the normal human brain. Since the protocols described here have been used to isolate both PrPSc from infected brains and iPrPC from uninfected brains, they provide us with an opportunity to compare differences in physicochemical features, neurotoxicity, and infectivity between the two isoforms. Such a study will greatly improve our understanding of the infectious proteinaceous pathogens. The physiology and pathophysiology of iPrPC are unclear at present. Notably, in a newly-identified human prion disease termed variably protease-sensitive prionopathy, we found a new PrPSc that shares the immunoreactive behavior and fragmentation with iPrPC 11, 12. Moreover, we recently demonstrated that iPrPC is the main species that interacts with amyloid-&beta; protein in Alzheimer disease13. In the same study, these methods were used to isolate Abeta aggregates and oligomers in Alzheimer's disease13, suggesting their application to non-prion protein aggregates involved in other neurodegenerative disorders.

A new species of cellular prion protein (PrPC) has recently been identified in uninfected human brains using the methods described here. These methods can be used to isolate various PrP species, while some of them are also useful in isolating other misfolded protein aggregates from human brains.

在正常人脑分离的可溶性和不溶性朊蛋白低聚物

The central event in the pathogenesis of prion diseases involves a conversion of the host-encoded cellular prion protein PrPC into its pathogenic isoform ...

The Use of Primary Human Fibroblasts for Monitoring Mitochondrial Phenotypes in the Field of Parkinson's Disease

Parkinson's disease (PD) is the second most common movement disorder and affects 1% of people over the age of 60 1. Because ageing is the most important risk factor, cases of PD will increase during the next decades 2. Next to pathological protein folding and impaired protein degradation pathways, alterations of mitochondrial function and morphology were pointed out as further hallmark of neurodegeneration in PD 3-11.
After years of research in murine and human cancer cells as in vitro models to dissect molecular pathways of Parkinsonism, the use of human fibroblasts from patients and appropriate controls as ex vivo models has become a valuable research tool, if potential caveats are considered. Other than immortalized, rather artificial cell models, primary fibroblasts from patients carrying disease-associated mutations apparently reflect important pathological features of the human disease.
Here we delineate the procedure of taking skin biopsies, culturing human fibroblasts and using detailed protocols for essential microscopic techniques to define mitochondrial phenotypes. These were used to investigate different features associated with PD that are relevant to mitochondrial function and dynamics. Ex vivo, mitochondria can be analyzed in terms of their function, morphology, colocalization with lysosomes (the organelles degrading dysfunctional mitochondria) and degradation via the lysosomal pathway. These phenotypes are highly relevant for the identification of early signs of PD and may precede clinical motor symptoms in human disease-gene carriers. Hence, the assays presented here can be utilized as valuable tools to identify pathological features of neurodegeneration and help to define new therapeutic strategies in PD.

The Use of Primary Human Fibroblasts for Monitoring Mitochondrial Phenotypes in the Field of Parkinson&#039;s Disease

Fibroblasts from patients carrying mutations in Parkinson's disease-causing genes represent an easily accessible ex vivo model to study disease-associated phenotypes. Live cell imaging gives the opportunity to study morphological and functional parameters in living cells. Here we describe the preparation of human fibroblasts and subsequent monitoring of mitochondrial phenotypes.

利用人类纤维原细胞线粒体表型的监测领域的帕金森氏病

Parkinson's disease (PD) is the second most  common movement disorder and affects 1% of people over the age of 60 1. Because ageing is  the most important ...

Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease

Lipoxygenase (LOX) activity has been implicated in neurodegenerative disorders such as Alzheimer&#39;s disease, but its effects in Parkinson&#39;s disease (PD) pathogenesis are less understood. Gene-environment interaction models have utility in unmasking the impact of specific cellular pathways in toxicity that may not be observed using a solely genetic or toxicant disease model alone.&#160;To evaluate if distinct LOX isozymes selectively contribute to PD-related neurodegeneration, transgenic (i.e. 5-LOX and 12/15-LOX deficient) mice can be challenged with a toxin that mimics cell injury and death in the disorder.&#160;Here we describe the use of a neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces a nigrostriatal lesion to elucidate the distinct contributions of LOX isozymes to neurodegeneration related to PD. The use of MPTP in mouse, and nonhuman primate, is well-established to recapitulate the nigrostriatal damage in PD.&#160;The extent of MPTP-induced lesioning is measured by HPLC analysis of dopamine and its metabolites and semi-quantitative Western blot analysis of striatum for tyrosine hydroxylase (TH), the rate-limiting enzyme for the synthesis of dopamine. To assess inflammatory markers, which may demonstrate LOX isozyme-selective sensitivity, glial fibrillary acidic protein (GFAP) and Iba-1 immunohistochemistry are performed on brain sections containing substantia nigra, and GFAP Western blot analysis is performed on striatal homogenates.&#160;This experimental approach can provide novel insights into gene-environment interactions underlying nigrostriatal degeneration and PD.

Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson&#039;s Disease

Lipoxygenase (LOX) isozymes can generate products that may increase or decrease neuroinflammation and neurodegeneration.&#160;A gene-environment interaction study could identify LOX isozyme-specific effects. Using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of nigrostriatal damage in two LOX isozyme-deficient transgenic lines allows for comparison of the contribution of LOX isozymes on dopaminergic integrity and inflammation.

基因-环境相互作用模型揭开帕金森病的隐形易感机制

Lipoxygenase (LOX) activity has been implicated in neurodegenerative disorders such as Alzheimer&#39;s disease, but its effects in Parkinson&#39;s disease ...

Excitotoxic Stimulation of Brain Microslices as an In vitro Model of Stroke

Examining molecular mechanisms involved in neuropathological conditions, such as ischemic stroke, can be difficult when using whole animal systems. As such, primary or &#39;neuronal-like&#39; cell culture systems are commonly utilized. While&#160;these systems are relatively easy to work with, and are useful model systems in which various functional outcomes (such as cell death) can be readily quantified, the examined outcomes and pathways in cultured immature neurons (such as excitotoxicity-mediated cell death pathways) are not necessarily the same as those observed in mature brain, or in intact tissue. Therefore, there is the need to develop models in which cellular mechanisms in mature neural tissue can be examined. We have developed an in vitro technique that can be used to investigate a variety of molecular pathways in intact nervous tissue. The technique described herein utilizes rat cortical tissue, but this technique can be adapted to use tissue from a variety of species (such as mouse, rabbit, guinea pig, and chicken) or brain regions (for example, hippocampus, striatum, etc.). Additionally, a variety of stimulations/treatments can be used (for example, excitotoxic, administration of inhibitors, etc.). In conclusion, the brain slice model described herein can be used to examine a variety of molecular mechanisms involved in excitotoxicity-mediated brain injury.

Excitotoxic Stimulation of Brain Microslices as an In vitro Model of Stroke

We have developed a brain slice model which can be used to examine molecular mechanisms involved in excitotoxicity-mediated brain injury.&#160;This technique generates viable mature brain tissue and reduces animal numbers required for experimentation, whilst keeping the neuronal circuitry, cellular interactions, and postsynaptic compartments partly intact.

脑Microslices的兴奋性刺激作为<em&gt;在体外</em&gt;中风模型

Examining molecular mechanisms involved in neuropathological conditions, such as ischemic stroke, can be difficult when using whole animal systems. As ...

Using Saccadometry with Deep Brain Stimulation to Study Normal and Pathological Brain Function

The oculomotor system involves a large number of brain areas including parts of the basal ganglia, and various neurodegenerative diseases including Parkinson's and Huntington's can disrupt it. People with Parkinson's disease, for example, tend to have increased saccadic latencies. Consequently, the quantitative measurement of saccadic eye movements has received considerable attention as a potential biomarker for neurodegenerative conditions. A lot more can be learned about the brain in both health and disease by observing what happens to eye movements when the function of specific brain areas is perturbed. Deep brain stimulation is a surgical intervention used for the management of a range of neurological conditions including Parkinson's disease, in which stimulating electrodes are placed in specific brain areas including several sites in the basal ganglia. Eye movement measurements can then be made with the stimulator systems both off and on and the results compared. With suitable experimental design, this approach can be used to study the pathophysiology of the disease being treated, the mechanism by which DBS exerts it beneficial effects, and even aspects of normal neurophysiology.

This paper describes the use of quantitative measurement of eye movements in conjunction with stimulation of focal areas of the deep brain in order to study physiology, pathophysiology, and the mechanisms of deep brain stimulation.

使用Saccadometry与深部脑刺激来研究正常和病理脑功能

The oculomotor system involves a large number of brain areas including parts of the basal ganglia, and various neurodegenerative diseases including ...

Development of an Alpha-synuclein Based Rat Model for Parkinson's Disease via Stereotactic Injection of a Recombinant Adeno-associated Viral Vector

In order to study the molecular pathways of Parkinson&#39;s disease (PD) and to develop novel therapeutic strategies, scientific investigators rely on animal models. The identification of PD-associated genes has led to the development of genetic PD models. Most transgenic &#945;-SYN mouse models develop gradual &#945;-SYN pathology but fail to display clear dopaminergic cell loss and dopamine-dependent behavioral deficits. This hurdle was overcome by direct targeting of the substantia nigra with viral vectors overexpressing PD-associated genes. Local gene delivery using viral vectors provides an attractive way to express transgenes in the central nervous system. Specific brain regions can be targeted (e.g. the substantia nigra), expression can be induced in the adult setting and high expression levels can be achieved. Further, different vector systems based on various viruses can be used. The protocol outlines all crucial steps to perform a viral vector injection in the substantia nigra of the rat to develop a viral vector-based alpha-synuclein animal model for Parkinson&#39;s disease.

Development of an Alpha-synuclein Based Rat Model for Parkinson&#039;s Disease via Stereotactic Injection of a Recombinant Adeno-associated Viral Vector

This manuscript describes how viral vector-mediated local gene delivery provides an attractive way to express transgenes in the central nervous system. The protocol outlines all crucial steps to perform a viral vector injection in the substantia nigra of the rat to develop a viral vector-based animal model for Parkinson's disease.

通过重组腺相关病毒载体注射立体的α-突触核蛋白基于大鼠模型为帕金森氏病的发展

In order to study the molecular pathways of Parkinson&#39;s disease (PD) and to develop novel therapeutic strategies, scientific investigators rely on ...