The authors would like to thank Emily L. Thorn, B.A., for her assistance with the Source estimation of evoked electrical activity Section. MMS was supported by a KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award KL2 TR001100). CJC was supported by a grant from the National Institutes of Health (5K12NS066225). APL was supported in part by grants from the Sidney R. Baer Jr. Foundation, the National Institutes of Health (R01 HD069776, R01 NS073601, R21 MH099196, R21 NS082870, R21 NS085491, R21 HD07616), and Harvard Catalyst/The Harvard Clinical and Translational Science Center (NCRR and the NCATS, NIH UL1 RR025758). BSC was supported by the National Institute of Neurological Disorders and Stroke (R01 NS073601).

MMS, SWG, CJC and BSC have nothing to disclose. APL serves on the scientific advisory boards for Nexstim, Neuronix, Starlab Neuroscience, Neuroelectrics, and Neosync, and is listed as an inventor on several issued and pending patents on the real-time integration of transcranial magnetic stimulation (TMS) with electroencephalography (EEG) and magnetic resonance imaging (MRI).

静息态的功能连接的MRI已经被用于识别网络连接在人的大脑，并以确定发生在不同的疾病状态26,31,32连接的改变。然而，如磁共振成像功能连接是基于在BOLD信号识别相关，以及作为血液氧合变化与底层神经活动，因果意义和这些功能磁共振成像连接的发现的生理相关性的非平凡关系目前还不清楚。 TMS能够在特定皮层区域大脑活动的空间和时间上定位的操作;当与脑电图结合，TMS可以用来评估大脑的不同脑区的刺激的响应。因此，TMS脑电图可应用于区域具有改变的功能磁共振成像功能连接，以评估在连接的观察变化是否有可能与潜在疾病病理生理学的生理相关性。本文介绍了使用连接引导TMS-EEG评估癫痫患者皮质兴奋性的协议，由于大脑的发育，脑室周围异位结节，这是不正常的功能连接网络37的发展相关的畸形。该协议是用来证明，患者的活动性癫痫有皮质兴奋特定于与改变静息态功能磁共振成像功能连接的区域，以及过度兴奋可以在一个单独的学科水平进行评估。在与先前脑电图捕获发作的患者，异常迟TMS诱发活性被看作在同一区域（远离刺激位点）从该患者的癫痫发作起源，表明异常功能连接的区域是确实的部分癫痫发作产生的网络。 有许多的成功关键步骤该协议的完成。与静息态功能磁共振数据采集，高品质的静息状态数据和经验，RS-fcMRI数据处理和分析技术的专业技术是准确测定基于连接的目标至关重要。在设计和执行TMS脑电图研究中另一个重要的制约因素是TMS兼容脑电设备的需求;此外，对于研究的地方精确瞄准是非常关键的，神经导航设备也是必要的。另一个限制是，TMS往往产生大量的脑电图工件，刺激在额极和侧颞区域特别是当，因此，可能难以在刺激目标位于在这些区域中，以获得高质量的数据。数据收集和脑电图记录过程中也需要进行优化，以尽量减少脑电信号的文物，和实验最好应通过熟悉的脑电数据的人员进行运行，以便文物，做到出现（ 例如 ，便便- [R阻抗导电胶晾干），可以快速识别并最小化。一个重要的步骤包括展示眨眼，肌肉收缩和运动对脑电图的研究课题的影响，因为这可能是在帮助主题的理解和减少这些类型的工件的关键。 另一个重要的考虑是生物制品，可能会限制结果的解释的最小化。一个特别重要的，例如生物工件是听觉诱发电位由TMS线圈"点击"，这是众所周知的向TMS诱发电位，特别是在100和180毫秒55,67,68时的TMS的大小产生-evoked潜力也典型地是最大的。已显示，以尽量减少在TMS听觉诱发电位的一种方法是噪声通过使用白色或有色噪声掩蔽，增加泡沫体的线圈和头皮10,55之间薄层的</s了&gt;。在不存在这样的噪声掩蔽的，在TMS听觉诱发电位差可能有助于在受试者群体之间的诱发活性差异（虽然不是在受试者内的不同点之间的诱发电位所观察到的差异。） 最后，即使小心，以优化记录，显著预处理往往是必要的，以回收干净的数据进行分析。幸运的是，除去TMS-EEG记录文物验证的方法已经公布60;然而，即使使用这些技术，非常早期的信号（&lt;15毫秒）的恢复可能是非常困难或不可靠的。一个额外的挑战是，脑电图数据是高维和复杂，因此，一个清晰的现有假说是常常需要提取有意义的信息。此外，因为TMS效果和EEG信号可以显著因为广泛的是非脑因子的受试者之间变化很难或者不可能控制（ 例如 ，颅骨的厚度，头骨皮层的距离，合并用药，睡眠质量的前一夜），结果措施上诱发反应的原始大小的依赖很可能是更多的信息或意义。 虽然技术上具有挑战性，RS-fcMRI，TMS和EEG的融合到一起在一个实验中实现了各种各样关于皮质生理特定连接的发现意义的假设测试。在疾病状态下，这些技术可以整合到一起，评估fMRI的网络连通性的变化，皮质兴奋和诱发大脑活动的病理生理改变和疾病表现之间的关系。值得注意的是，这个协议可以用于研究通过共同结果测量皮质生理学即使当不正常的连接的焦点（并因此刺激区域）从一个受另一个，providi不同纳克的输出可能在个别科目层面有意义的，开放的个性化的方式来调查和最终处理的可能性。 在这项研究中所描述的协议也可以扩展到评估不同学科组的皮质生理的特定功能。例如，最近的一些研究已经表明，在TMS诱发脑电图响应的N45分量表示的GABA-A受体69的活性，而在TMS诱发脑电图响应的N100组分是GABA-B介导的抑制的量度21,69。双脉冲TMS-脑电图具有长间隔内抑制协议提供GABA能活性的另一项措施，并已被证明在额叶区域的患者相对于对照70精神分裂症被改变。因此，上述协议可以修改，以专门解决与改变泛函有关GABA能活动问题的地区升连接。此外，在TMS诱发电位峰源定位可以识别由刺激从事遥远的地区，从而有助于该通知由传统的静息态功能磁共振成像识别功能的连接能传输因果诱发活动。对于其中的关键网络集线器深的情况下，RS-fcMRI也可以使用，以确定对刺激访问皮层的目标，并由此使参与正常的现象，在疾病状态35,36,71大脑特定网络的调制。在这种情况下，在这项研究中所描述的技术可以用于前，以评估局部和分布式单脉冲TMS诱发活性和重复可塑性协议之后，确定可塑性协议是否确实已改变局部皮质兴奋性，和/或网络兴奋远端。 综上所述，RS-fcMRI，TMS和脑电图的集成使explorati在如何大脑连接的影响皮质生理和行为在人类科目。此外，这些技术也可以结合，以评估在连接的改变如何，涉及到的病理生理学疾病状态如在上述的协议说明。

经颅磁刺激（TMS）是通过电磁感应非侵入性刺激皮质区域的装置。在TMS，一个大的但在空间上受限的磁通用于诱导靶皮层区的电场，并由此调节底层神经组织的活性。 TMS在运动皮层运动诱发的结果，可以通过外围肌电图（EMG）来测量电势。当成对或脉冲三胞胎施加，TMS可以用来评估特定皮质内GABA能和谷氨酸能电路1-3的活性，从而评估兴奋和抑制体内在人类患者中的平衡。在癫痫具体地说，TMS的研究表明，皮质兴奋存在癫痫患者4,5，并且可以与成功的抗癫痫药物治疗正常化，从而预测对药物的反应6。此外，前皮质的TMS措施citability显示在患者的中间值与单一发作7和患者都特发性和获得性局灶性癫痫8兄弟姐妹。这些结果表明，大脑皮层兴奋的TMS措施可能使我们确定癫痫内表。然而，这些措施的敏感性和特异性是有限的，可能是因为TMS-EMG只能与运动皮层电路刺激进行评估，许多癫痫患者有运动皮层外扣押灶。 脑电图（EEG）提供了直接测量对于TMS脑反应的机会，并且可以使用跨越新皮质的广泛领域，以评估脑反应性。有研究整合脑电图（TMS-EEG）TMS表明，TMS产生整个皮层9,10的反响，并且是可重复的，可靠的11-13活动的浪潮。通过评估诱发活性的传播在不同的行为的状态和在不同的任务，TMS脑电图已用于因果探查人类大脑的网络10,14-16的动态有效连接。 TMS-EEG措施，对疾病从精神分裂症17多动症18所示显著异常，意识障碍如持续性植物状态19。此外，一些团体已经确定了双脉冲的EEG相关因素TMS-EMG指标是癫痫患者的异常20,21。特别重要的，以前的研究也表明，异常刺激诱发的脑电活动被认为是在癫痫患者22-25。 评价的脑电路的另一手段是通过静息态的功能连接的MRI（RS-fcMRI），即在血液氧合水平随时间评估的相关性，从不同脑区26依赖性（BOLD）的信号的技术。利用研究RS-fcMRI已经证明，人的大脑组织成相互作用区域26-29的不同的网络，可以由RS-fcMRI 30确定的具体的大型分布式神经网络内发生的神经精神性疾病，以及经由RS-标识的大脑网络fcMRI往往是神经精神疾病状态31,32异常。在潜在的临床应用方面，RS-fcMRI具有比传统的基于任务的功能磁共振成像应用33几个优点，包括对主体合作的依赖，并在变量上表现的关注。因此，最近有研究探索在不同疾病状态RS-fcMRI变化爆炸。然而，RS-fcMRI的局限之一是在确定是否以及如何在BOLD信号相关性（或anticorrelations）用于形成神经元沟通的基础的电相互作用的难度。一个相关的问题是，它是ofteÑ不清楚是否在各种疾病状态看到的RS-fcMRI变化有生理意义。特别是关于癫痫，目前还不清楚的RS-fcMRI异常是否只是为了间痫样瞬变到期，或独立存在这样的电生理异常;需要同时EEG-fMRI来帮助这些可能性34之间评估。 如TMS可用于产生不同的皮层区域的激活瞬时或持续变化，TMS研究提供的因果评估不同静息态功能磁共振成像连接图案的意义的装置。一种方法是使用RS-fcMRI引导在不同的疾病状态的治疗的刺激的努力;它可以预期的TMS定位到该被功能地连接到已知参与不同疾病状态是更可能比TMS靶向区域没有这种函数的治疗有效区域的区域最终的连接，而事实上一些研究发现，初步证据显示此35,36。另一种方法是涉及使用TMS-脑电图因果关系评估不同的静息态fcMRI模式的生理意义。具体地，可以测试，显示在一个特定的疾病状态异常功能连接区应该显示在患者刺激不同的响应比在健康受试者的假设，并且这些生理异常是存在特异性（或主要）与的异常刺激连通区域。 为了说明上述情况，我们由于大脑发育异常结节性脑室周围异位（PNH）37提供最近的一项研究中，RS-fcMRI，TMS和脑电图合并探索癫痫患者皮质兴奋的一个例子。 PNH患者与adolescent-或成人发病的癫痫临床目前，阅读障碍，和正常INTElligence，并有相邻于影像学38,39侧脑室灰质异常结节。以前的研究已经表明，异位灰质这些脑室结节结构上和功能上连接到离散的病灶中的新皮层40,41，并且癫痫发作可以由新皮层区域，灰质异位，或两者同时进行42发出，表明在癫痫这些患者是电路的现象。通过使用静息状态FC-MRI引导TMS脑电图，我们表明，患者的活动性癫痫是由于PNH有皮质过度兴奋的迹象，而这似乎兴奋只限于地区异常功能连接到深的结节。 该协议是在两个单独的会话进行的。在第一届会议上，结构和静息状态下血液氧合水平依赖（BOLD）对比MRI序列被收购（病人），或只是结构性MRI序列（为正常对照组）。在第一和第二会话之间，静息态功能连接分析用于定义为患者的大脑皮质的目标，和MNI坐标获得这些目标。然后，相当于皮质的目标（根据MNI坐标）被确定为每个健康对照者。在第二届会议上，获得了TMS-EEG数据。 在本文给出的实例中，使用内部软件工具箱和在MRI软件43,44进行官能连通的MRI分析。神经导航的TMS与具有实时磁共振神经导航经颅磁刺激进行。脑电图记录，具有60个通道的TMS兼容的系统，它利用一个取样与保持电路由TMS的，以避免放大器饱和。使用MATLAB R201运行自定义脚本和EEGLAB工具箱45（版本12.0.2.4b）脑电数据进行分析2B。

<table border="0" cellpadding="0" cellspacing="0" width="573">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">3T MRI scanner</td>
			<td style="width:71px;"></td>
			<td style="width:119px;"></td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">MRI functional connectivity software</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">MRI image viewing software</td>
			<td></td>
			<td></td>
			<td>MRICron</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Transcranial Magnetic Stimulator</td>
			<td>Nexstim</td>
			<td>eXimia Stimulator&#160;</td>
			<td>Can use stimulators from other suppliers e.g. Magventure, Magstim</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">MRI neuronavigation system</td>
			<td>Nexstim</td>
			<td>NBS v3.2.1</td>
			<td>Alternative MRI neuronavigation system e.g. Brainsight, Localite</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">TMS-compatible EEG system</td>
			<td>Nexstim</td>
			<td>Eximia EEG</td>
			<td>Alternatives: Brain Products, Synamps, ANT</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Matlab</td>
			<td>Mathworks</td>
			<td>R2012b</td>
			<td>Alternatives: Octave</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">EEGLab</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr height="21">
			<td colspan="2" height="21" style="height:21px;">Minimum Norm Estimate (MNE) software</td>
			<td></td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">FreeSurfer</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
	</tbody>
</table>

a multimodal imaging- and stimulation-based method of evaluating connectivity-related brain excitability in patients with epilepsy

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

静息态功能连接功能磁共振成像可用于识别证明与异位脑室周围灰质结节高功能连接皮层区域（ 图1），以及控制区域没有这种连接。为了确定这种不正常的功能连接是否具有生理意义，与相关静息态活性皮质区域可以选择为neuronavigated TMS的"连接"的目标网站，并诱发脑电图结果相比，通过控制刺激产生的脑电位在同一患者的非相连的目标。此外，同一区域可以在健康对照受试者（ 图2）定位到确定在PNH患者看到的异常功能连接是否具有用于患者的临床癫痫综合征的病理生理学意义。具体地，皮质hyperex的存在citability可以在个体患者水平通过确定全局平均势场的归一化下面积的曲线，然后评估该值是否是用于癫痫患者比他或她的匹配的对照（ 图2）放大来评估。在癫痫患者可以识别从该异常活性发生的脑区TMS诱发电位异常晚期峰的源定位，并且可以在空间上与患者的癫痫发作焦点（ 图3）共定位。 <img alt="图1" src="/files/ftp_upload/53727/53727fig1.jpg" /> 图1.静息态功能连通性和TMS目标。（A，B）与功能活化显著相关区（蓝/绿）的两个病人脑室周围结节性异位和癫痫到静止状态的BOLD信号在异位结节。 <s仲&gt;（C，D）的连接的目标部位（红色）和这两个患者在非连接目标部位（蓝色）。 （改性许可沙菲等人 ，2015年37）。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53727/53727fig1large.jpg" target="_blank">请点击此处查看该图的放大版本。</a> <img alt="图2" src="/files/ftp_upload/53727/53727fig2.jpg" /> 图2. TMS诱发电位和全球平均场电位。（A）通过与PNH和癫痫病人连接的目标刺激产生的TMS诱发电位。（B），由同一刺激产生的TMS诱发电位区域在上述患者的相匹配的健康对照受试者（C）由连接和非连接的目标的刺激该患者产生的全球平均场电位（GMFP）<html>和他匹配的对照。（D）归由该主题对的连接和非连接的目标刺激产生的GMFP的面积下的曲线。 <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53727/53727fig2large.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/53727/53727fig3.jpg" /> 图3. TMS诱发活动及检取声母的源定位。 （A）癫痫患者的后期TMS诱发峰源电子成像效果;规模是所估计的电流乘以10 -11。在这同一患者先前捕获的发作起始的（B）的电气源的成像效果。 （改性许可沙菲等人，2015年37）T ="_空白"&gt;点击此处查看该图的放大版本。

Watch this Scientific Journal Video about A Multimodal Imaging- and Stimulation-based Method of Evaluating Connectivity-related Brain Excitability in Patients with Epilepsy at JoVE.com

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

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

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

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

a-multimodal-imaging-stimulation-based-method-evaluating-connectivity

Nanyang Technological University

Research

JoVE Journal

Medicine

11.0K 次观看.  Harvard Medical School. Resting-state functional-connectivity MRI has identified abnormalities in patients with a wide range of neuropsychiatric disorders, including epilepsy due to malformations of cortical development. Transcranial Magnetic Stimulation in combination with EEG can demonstrate that patients with epilepsy have cortical hyperexcitability in regions with abnormal connectivity. 

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

In vivo Near Infrared Fluorescence (NIRF) Intravascular Molecular Imaging of Inflammatory Plaque, a Multimodal Approach to Imaging of Atherosclerosis

The vascular response to injury is a well-orchestrated inflammatory response triggered by the accumulation of macrophages within the vessel wall leading to an accumulation of lipid-laden intra-luminal plaque, smooth muscle cell proliferation and progressive narrowing of the vessel lumen. The formation of such vulnerable plaques prone to rupture underlies the majority of cases of acute myocardial infarction. The complex molecular and cellular inflammatory cascade is orchestrated by the recruitment of T lymphocytes and macrophages and their paracrine effects on endothelial and smooth muscle cells.1
Molecular imaging in atherosclerosis has evolved into an important clinical and research tool that allows in vivo visualization of inflammation and other biological processes. Several recent examples demonstrate the ability to detect high-risk plaques in patients, and assess the effects of pharmacotherapeutics in atherosclerosis.4 While a number of molecular imaging approaches (in particular MRI and PET) can image biological aspects of large vessels such as the carotid arteries, scant options exist for imaging of coronary arteries.2 The advent of high-resolution optical imaging strategies, in particular near-infrared fluorescence (NIRF), coupled with activatable fluorescent probes, have enhanced sensitivity and led to the development of new intravascular strategies to improve biological imaging of human coronary atherosclerosis.
Near infrared fluorescence (NIRF) molecular imaging utilizes excitation light with a defined band width (650-900 nm) as a source of photons that, when delivered to an optical contrast agent or fluorescent probe, emits fluorescence in the NIR window that can be detected using an appropriate emission filter and a high sensitivity charge-coupled camera. As opposed to visible light, NIR light penetrates deeply into tissue, is markedly less attenuated by endogenous photon absorbers such as hemoglobin, lipid and water, and enables high target-to-background ratios due to reduced autofluorescence in the NIR window. Imaging within the NIR 'window' can substantially improve the potential for in vivo imaging.2,5
Inflammatory cysteine proteases have been well studied using activatable NIRF probes10, and play important roles in atherogenesis. Via degradation of the extracellular matrix, cysteine proteases contribute importantly to the progression and complications of atherosclerosis8. In particular, the cysteine protease, cathepsin B, is highly expressed and colocalizes with macrophages in experimental murine, rabbit, and human atheromata.3,6,7 In addition, cathepsin B activity in plaques can be sensed in vivo utilizing a previously described 1-D intravascular near-infrared fluorescence technology6, in conjunction with an injectable nanosensor agent that consists of a poly-lysine polymer backbone derivatized with multiple NIR fluorochromes (VM110/Prosense750, ex/em 750/780nm, VisEn Medical, Woburn, MA) that results in strong intramolecular quenching at baseline.10 Following targeted enzymatic cleavage by cysteine proteases such as cathepsin B (known to colocalize with plaque macrophages), the fluorochromes separate, resulting in substantial amplification of the NIRF signal. Intravascular detection of NIR fluorescence signal by the utilized novel 2D intravascular NIRF catheter now enables high-resolution, geometrically accurate in vivo detection of cathepsin B activity in inflamed plaque.
In vivo molecular imaging of atherosclerosis using catheter-based 2D NIRF imaging, as opposed to a prior 1-D spectroscopic approach,6 is a novel and promising tool that utilizes augmented protease activity in macrophage-rich plaque to detect vascular inflammation.11,12 The following research protocol describes the use of an intravascular 2-dimensional NIRF catheter to image and characterize plaque structure utilizing key aspects of plaque biology. It is a translatable platform that when integrated with existing clinical imaging technologies including angiography and intravascular ultrasound (IVUS), offers a unique and novel integrated multimodal molecular imaging technique that distinguishes inflammatory atheromata, and allows detection of intravascular NIRF signals in human-sized coronary arteries.

In vivo Near Infrared Fluorescence NIRF Intravascular Molecular Imaging of Inflammatory Plaque, a Multimodal Approach to Imaging of Atherosclerosis

We detail a new near-infrared fluorescence (NIRF) catheter for 2-dimensional intravascular molecular imaging of plaque biology in vivo. The NIRF catheter can visualize key biological processes such as inflammation by reporting on the presence of plaque-avid activatable and targeted NIR fluorochromes. The catheter utilizes clinical engineering and power requirements and is targeted for application in human coronary arteries. The following research study describes a multimodal imaging strategy that utilizes a novel in vivo intravascular NIRF catheter to image and quantify inflammatory plaque in proteolytically active inflamed rabbit atheromata.

体内近红外荧光（NIRF）血管内分子成像炎性斑块，多式联运方针成像动脉粥样硬化

The vascular response to injury is a well-orchestrated inflammatory response triggered by the accumulation of macrophages within the vessel wall leading ...

科研

医学

Driving Simulation in the Clinic: Testing Visual Exploratory Behavior in Daily Life Activities in Patients with Visual Field Defects

Patients suffering from homonymous hemianopia after infarction of the posterior cerebral artery (PCA) report different degrees of constraint in daily life, despite similar visual deficits. We assume this could be due to variable development of compensatory strategies such as altered visual scanning behavior. Scanning compensatory therapy (SCT) is studied as part of the visual training after infarction next to vision restoration therapy. SCT consists of learning to make larger eye movements into the blind field enlarging the visual field of search, which has been proven to be the most useful strategy1, not only in natural search tasks but also in mastering daily life activities2. Nevertheless, in clinical routine it is difficult to identify individual levels and training effects of compensatory behavior, since it requires measurement of eye movements in a head unrestrained condition. Studies demonstrated that unrestrained head movements alter the visual exploratory behavior compared to a head-restrained laboratory condition3. Martin et al.4 and Hayhoe et al.5 showed that behavior demonstrated in a laboratory setting cannot be assigned easily to a natural condition. Hence, our goal was to develop a study set-up which uncovers different compensatory oculomotor strategies quickly in a realistic testing situation: Patients are tested in the clinical environment in a driving simulator. SILAB software (Wuerzburg Institute for Traffic Sciences GmbH (WIVW)) was used to program driving scenarios of varying complexity and recording the driver's performance. The software was combined with a head mounted infrared video pupil tracker, recording head- and eye-movements (EyeSeeCam, University of Munich Hospital, Clinical Neurosciences).
The positioning of the patient in the driving simulator and the positioning, adjustment and calibration of the camera is demonstrated. Typical performances of a patient with and without compensatory strategy and a healthy control are illustrated in this pilot study. Different oculomotor behaviors (frequency and amplitude of eye- and head-movements) are evaluated very quickly during the drive itself by dynamic overlay pictures indicating where the subjects gaze is located on the screen, and by analyzing the data. Compensatory gaze behavior in a patient leads to a driving performance comparable to a healthy control, while the performance of a patient without compensatory behavior is significantly worse. The data of eye- and head-movement-behavior as well as driving performance are discussed with respect to different oculomotor strategies and in a broader context with respect to possible training effects throughout the testing session and implications on rehabilitation potential.

Patients with visual deficits after stroke report about different constraints in daily life most likely due to variable compensatory strategies, which are difficult to differentiate in clinical routine. We present a clinical set-up which allows measurement of different compensatory head- and eye-movement-strategies and evaluating their effects on driving performance.

驾驶模拟诊所:测试视觉与视野缺损的患者在日常活动中的探索行为

Patients suffering from homonymous hemianopia after infarction of the posterior cerebral artery (PCA) report different degrees of constraint in daily ...

Computerized Dynamic Posturography for Postural Control Assessment in Patients with Intermittent Claudication

Computerized dynamic posturography with the EquiTest is an objective technique for measuring postural strategies under challenging static and dynamic conditions. As part of a diagnostic assessment, the early detection of postural deficits is important so that appropriate and targeted interventions can be prescribed. The Sensory Organization Test (SOT) on the EquiTest determines an individual&#39;s use of the sensory systems (somatosensory, visual, and vestibular) that are responsible for postural control. Somatosensory and visual input are altered by the calibrated sway-referenced support surface and visual surround, which move in the anterior-posterior direction in response to the individual&#39;s postural sway. This creates a conflicting sensory experience. The Motor Control Test (MCT) challenges postural control by creating unexpected postural disturbances in the form of backwards and forwards translations. The translations are graded in magnitude and the time to recover from the perturbation is computed.
Intermittent claudication, the most common symptom of peripheral arterial disease, is characterized by a cramping pain in the lower limbs and caused by muscle ischemia secondary to reduced blood flow to working muscles during physical exertion. Claudicants often display poor balance, making them susceptible to falls and activity avoidance. The Ankle Brachial Pressure Index (ABPI) is a noninvasive method for indicating the presence of peripheral arterial disease and intermittent claudication, a common symptom in the lower extremities. ABPI is measured as the highest systolic pressure from either the dorsalis pedis or posterior tibial artery divided by the highest brachial artery systolic pressure from either arm. This paper will focus on the use of computerized dynamic posturography in the assessment of balance in claudicants.

Individuals with intermittent claudication exhibit poor balance compared to healthy controls. Computerized dynamic posturography is an objective method for measuring an individual's postural responses to balance disturbances. This provides an objective reflection of the person&#x2019;s ability to respond to situations under which sensory stimuli are altered and unexpected perturbations occur.

Computerized dynamic posturography with the EquiTest is an objective technique for measuring postural strategies under challenging static and dynamic ...

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

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

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

采用高分辨率脑电图记录脑源成像局灶性癫痫的临床前模型大鼠

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

A Pipeline for 3D Multimodality Image Integration and Computer-assisted Planning in Epilepsy Surgery

Epilepsy surgery is challenging and the use of 3D multimodality image integration (3DMMI) to aid presurgical planning is well-established. Multimodality image integration can be technically demanding, and is underutilised in clinical practice. We have developed a single software platform for image integration, 3D visualization and surgical planning. Here, our pipeline is described in step-by-step fashion, starting with image acquisition, proceeding through image co-registration, manual segmentation, brain and vessel extraction, 3D visualization and manual planning of stereoEEG (SEEG) implantations. With dissemination of the software this pipeline can be reproduced in other centres, allowing other groups to benefit from 3DMMI. We also describe the use of an automated, multi-trajectory planner to generate stereoEEG implantation plans. Preliminary studies suggest this is a rapid, safe and efficacious adjunct for planning SEEG implantations. Finally, a simple solution for the export of plans and models to commercial neuronavigation systems for implementation of plans in the operating theater is described. This software is a valuable tool that can support clinical decision making throughout the epilepsy surgery pathway.

We describe the steps to use our custom designed software for image integration, visualization and planning in epilepsy surgery.

管道在癫痫手术3D多模图像集成和计算机辅助规划

Epilepsy surgery is challenging and the use of 3D multimodality image integration (3DMMI) to aid presurgical planning is well-established. Multimodality ...

Multimodal Quantitative Phase Imaging with Digital Holographic Microscopy Accurately Assesses Intestinal Inflammation and Epithelial Wound Healing

The incidence of inflammatory bowel disease, i.e., Crohn&#39;s disease and Ulcerative colitis, has significantly increased over the last decade. The etiology of IBD remains unknown and current therapeutic strategies are based on the unspecific suppression of the immune system. The development of treatments that specifically target intestinal inflammation and epithelial wound healing could significantly improve management of IBD, however this requires accurate detection of inflammatory changes. Currently, potential drug candidates are usually evaluated using animal models in vivo or with cell culture based techniques in vitro. Histological examination usually requires the cells or tissues of interest to be stained, which may alter the sample characteristics and furthermore, the interpretation of findings can vary by investigator expertise. Digital holographic microscopy (DHM), based on the detection of optical path length delay, allows stain-free quantitative phase contrast imaging. This allows the results to be directly correlated with absolute biophysical parameters. We demonstrate how measurement of changes in tissue density with DHM, based on refractive index measurement, can quantify inflammatory alterations, without staining, in different layers of colonic tissue specimens from mice and humans with colitis. Additionally, we demonstrate continuous multimodal label-free monitoring of epithelial wound healing in vitro, possible using DHM through the simple automated determination of the wounded area and simultaneous determination of morphological parameters such as dry mass and layer thickness of migrating cells. In conclusion, DHM represents a valuable, novel and quantitative tool for the assessment of intestinal inflammation with absolute values for parameters possible, simplified quantification of epithelial wound healing in vitro and therefore has high potential for translational diagnostic use.

Accurate assessment of anti-inflammatory effects is of utmost importance for the evaluation of potential new drugs for the treatment of inflammatory bowel disease. Digital holographic microscopy provides assessment of inflammation in murine and human colonic tissue samples as well as automated multimodal evaluation of epithelial wound healing in vitro.

多式联运定量相成像数字全息显微准确评估肠道炎症和上皮伤口愈合

The incidence of inflammatory bowel disease, i.e., Crohn&#39;s disease and Ulcerative colitis, has significantly increased over the last decade. The ...

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

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

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

在耐药性颞叶癫痫患者卵圆孔电极记录的网络分析

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

Interictal High Frequency Oscillations Detected with Simultaneous Magnetoencephalography and Electroencephalography as Biomarker of Pediatric Epilepsy

Crucial to the success of epilepsy surgery is the availability of a robust biomarker that identifies the Epileptogenic Zone (EZ). High Frequency Oscillations (HFOs) have emerged as potential presurgical biomarkers for the identification of the EZ in addition to Interictal Epileptiform Discharges (IEDs) and ictal activity. Although they are promising to localize the EZ, they are not yet suited for the diagnosis or monitoring of epilepsy in clinical practice. Primary barriers remain: the lack of a formal and global definition for HFOs; the consequent heterogeneity of methodological approaches used for their study; and the practical difficulties to detect and localize them noninvasively from scalp recordings. Here, we present a methodology for the recording, detection, and localization of interictal HFOs from pediatric patients with refractory epilepsy. We report representative data of HFOs detected noninvasively from interictal scalp EEG and MEG from two children undergoing surgery.
The underlying generators of HFOs were localized by solving the inverse problem and their localization was compared to the Seizure Onset Zone (SOZ) as this was defined by the epileptologists. For both patients, Interictal Epileptogenic Discharges (IEDs) and HFOs were localized with source imaging at concordant locations. For one patient, intracranial EEG (iEEG) data were also available. For this patient, we found that the HFOs localization was concordant between noninvasive and invasive methods. The comparison of iEEG with the results from scalp recordings served to validate these findings. To our best knowledge, this is the first study that presents the source localization of scalp HFOs from simultaneous EEG and MEG recordings comparing the results with invasive recordings. These findings suggest that HFOs can be reliably detected and localized noninvasively with scalp EEG and MEG. We conclude that the noninvasive localization of interictal HFOs could significantly improve the presurgical evaluation for pediatric patients with epilepsy.

High Frequency Oscillations (HFOs) have emerged as presurgical biomarkers for the identification of the epileptogenic zone in pediatric patients with medically refractory epilepsy. A methodology for the noninvasive recording, detection, and localization of HFOs with simultaneous scalp electroencephalography (EEG) and magnetoencephalography (MEG) is presented.

同时用脑磁图和脑电图为小儿癫痫的生物标志物检测发作间期高频振动

Crucial to the success of epilepsy surgery is the availability of a robust biomarker that identifies the Epileptogenic Zone (EZ). High Frequency ...

Whole-brain Segmentation and Change-point Analysis of Anatomical Brain MRI&#8212;Application in Premanifest Huntington's Disease

Recent advances in MRI offer a variety of useful markers to identify neurodegenerative diseases. In Huntington&#39;s disease (HD), regional brain atrophy begins many years prior to the motor onset (during the &#34;premanifest&#34; period), but the spatiotemporal pattern of regional atrophy across the brain has not been fully characterized. Here we demonstrate an online cloud-computing platform, &#34;MRICloud&#34;, which provides atlas-based whole-brain segmentation of T1-weighted images at multiple granularity levels, and thereby, enables us to access the regional features of brain anatomy. We then describe a regression model that detects statistically significant inflection points, at which regional brain atrophy starts to be noticeable, i.e. the &#34;change-point&#34;, with respect to a disease progression index. We used the CAG-age product (CAP) score to index the disease progression in HD patients. Change-point analysis of the volumetric measurements from the segmentation pipeline, therefore, provides important information of the order and pattern of structural atrophy across the brain. The paper illustrates the use of these techniques on T1-weighted MRI data of premanifest HD subjects from a large multicenter PREDICT-HD study. This design potentially has wide applications in a range of neurodegenerative diseases to investigate the dynamic changes of brain anatomy.

This paper describes a statistical model for volumetric MRI data analysis, which identifies the &#34;change-point&#34; when brain atrophy begins in premanifest Huntington&#39;s disease. Whole-brain mapping of the change-points is achieved based on brain volumes obtained using an atlas-based segmentation pipeline of T1-weighted images.

解剖性脑 MRI 的全脑分割及变化点分析--Premanifest 亨廷顿病的应用

Recent advances in MRI offer a variety of useful markers to identify neurodegenerative diseases. In Huntington&#39;s disease (HD), regional brain atrophy ...

Semi-quantitative Assessment Using [18F]FDG Tracer in Patients with Severe Brain Injury

Patients with severe traumatic brain injury (sTBI) have difficulty knowing whether they are accurately expressing their thoughts and emotions because of disorders of consciousness, disrupted higher brain function, and verbal disturbances. As a consequence of an insufficient ability to communicate, objective evaluations are needed from family members, medical staff, and caregivers. One such evaluation is the assessment of functioning brain areas. Recently, multimodal brain imaging has been used to explore the function of damaged brain areas. [18F]-fluorodeoxyglucose positron emission tomography-computed tomography ([18F]FDG-PET/CT) is a successful tool for examining brain function. However, the assessment of brain glucose metabolism based on [18F]FDG-PET/CT is not standardized and depends on several varying parameters, as well as the patient&#39;s condition. Here, we describe a series of semiquantitative assessment protocols for a region-of-interest (ROI) image analysis using self-produced [18F]FDG tracers in patients with sTBI. The protocol focuses on screening the participants, preparing the [18F]FDG tracer in the hot lab, scheduling the acquisition of [18F]FDG-PET/CT brain images, and measuring glucose metabolism using the ROI analysis from a targeted brain area.

Semi-quantitative Assessment Using [18F]FDG Tracer in Patients with Severe Brain Injury

[18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography is useful for studying glucose metabolism related to brain function. Here, we present a protocol for an [18F]FDG tracer set-up and semiquantitative assessment of the region-of-interest analysis for targeted brain areas associated with clinical manifestations in patients with severe traumatic brain injury.

[18f] fdg 示踪剂在重型颅脑损伤患者中的半定量评价

Patients with severe traumatic brain injury (sTBI) have difficulty knowing whether they are accurately expressing their thoughts and emotions because of ...