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Animal MRI/MRS Methodological Development for Drug Addiction Applications

用于药物成瘾应用的动物 MRI/MRS 方法开发

基本信息

批准号：
10267540
负责人：
Yihong Yang
金额：
$ 103.66万
依托单位：
NATIONAL INSTITUTE ON DRUG ABUSE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10267540
关键词：
Anatomy Animals Anterior Architecture Area Atlases Biological Psychiatry Brain Brain region Caliber Callithrix Cells Clinical Services Cues Data Devices Disease model Dose Drug Addiction Frequencies Functional Magnetic Resonance Imaging Generations Goals Heroin Human Implant Insula of Reil Location Longitudinal Studies Magnetic Resonance Imaging Maps Measurement Measures Medial Methodology Methods Microprocessor Monitor Morphologic artifacts Motor Motor Cortex Mus Network-based Neurobiology Neurons Output Pattern Penetration Performance Physiologic pulse Play Pre-Clinical Model Rattus Recording of previous events Reporting Research Rest Rodent Role Scalp structure Self Administration Signal Transduction Spottings Structure Substance Use Disorder System Techniques Testing Tracer Transcranial magnetic stimulation Transistors Width Withdrawal analog awake base cingulate cortex cranium design digital drug development electric field glucose analog glucose uptake improved magnetic field model development neurobiological mechanism neuroimaging neuropsychiatric disorder neuroregulation nonhuman primate novel novel strategies response tool voltage

项目摘要

1. Converging Structural and Functional Evidence for a Rat Salience Network The salience network (SN) is dysregulated in many neuropsychiatric disorders, including substance use disorder. Initially described in humans, identification of a rodent SN would provide the ability to mechanistically interrogate this network in preclinical models of neuropsychiatric disorders. We used modularity analysis on resting-state functional MRI data of rats (n=32) to parcellate rat insula into functional subdivisions and to identify a potential rat SN based on functional connectivity patterns from the insular subdivisions. We then used mouse tract tracing data from the Allen brain atlas to confirm the networks underlying structural connectivity. We next compared functional connectivity profiles of the SN across rat, marmoset (n=10) and humans (n=30). Finally, we assessed rat SNs response to conditioned cues in rats (n=21) with a history of heroin self-administration. We identified a putative rat SN, which consists of primarily the ventral anterior insula and anterior cingulate cortex, based on functional connectivity patterns from the ventral anterior insular division. Functional connectivity architecture of the rat SN is supported by the mouse neuronal tracer data. Moreover, the anatomical profile of the identified rat SN is similar to that of non-human primates and humans. Finally, we demonstrate that the rat SN responds to conditioned cues and increases functional connectivity to the Default Mode Network during conditioned heroin withdrawal. In conclusion, the neurobiological identification of a rat SN together with a demonstration of its functional relevance provides a novel platform with which to interrogate its functional significance in normative and neuropsychiatric disease models. (Tsai et al., Biological Psychiatry, in press) 2. Design of Focal Deep Transcranial Magnetic Stimulation Coil Conventional transcranial magnetic stimulation (TMS) coils are limited by the depth-focality tradeoff rule. The emission field intensity from coils with either small or large apertures will diverge quickly at less than one aperture diameter distance away from the coil. To utilize a better depth-focality tradeoff rule and accomplish deep and focused stimulation, a new approach needs to be employed. We have designed a new type of TMS coil that can deliver spot size adjustable stimulations to deeper brain regions. By comparing its stimulation depth and focality with 50 other coils, our study concluded the proposed method to have broken the depth-focality tradeoff rule. Both theoretical calculations and experimental data collectively demonstrated an adjustable focality controlled by the tuned angle of the coils conductive windings. Our TMS coil design plots a new curve in the depth-focality profile with better performance than all the existing conventional coil designs in the tradeoff rule. 3. Focal Transcranial Magnetic Stimulation in Awake Rats: Enhanced Glucose Uptake in Deep Cortical Layers Transcranial magnetic stimulation (TMS) is an emerging neuromodulation tool. However, preclinical models of TMS are limited. The aim of the study was to develop a method for performing TMS in awake rats and to characterize neuronal response to TMS by mapping glucose uptake following TMS administration. A headpost was implanted into rat skull serving as a refence to guide TMS target. Motor threshold measurement was used as the metric to assess the consistency in TMS delivery across animals and across sessions. Using a fluorescent glucose analogue (2-NBDG) as a marker of neuronal activity, we mapped glucose uptake in response to TMS of the rat motor cortex. Our results showed the average motor threshold (n = 41) was 34.6 6.3 % of maximum stimulator output (MSO). The variability of motor threshold across animals was similar to what has been reported in human studies. Furthermore, there was no significant difference in motor threshold measured across 3 separate days. Enhancement in fluorescent signals were TMS dose (power)-dependent, which centered around the motor cortex, covering an area medial-laterally 2 mm, rostral-caudally 4 mm at 55 % MSO, and 3 mm at 35 % MSO. The count of total cells with significant fluorescent signal was: 107 23 (55 % MSO), 73 11 (35 % MSO) and 42 11 (sham, 5% MSO). In conclusion, our method allows for consistent motor threshold assessment for longitudinal studies. Notably, cells with fluorescent signal enhancement were consistently aggregated in deep cortical layers, with minimal enhancement in superficial layers. To our knowledge, this is the first study of focal TMS in awake rodents. (Samantha et al., J. Neurosci Methods, 2020). 4. A Microprocessor-based Controlling System for Transcranial Magnetic Stimulation Transcranial magnetic stimulation (TMS) is a non-invasive technique for brain neurostimulation at specific cortical regions. During TMS, a waveform pulse stimulation is sent to a coil placed on the subjects scalp, in which the magnetic field generated by the coil induced an electric field in the brain cortex. Currently, the leading TMS research make efforts to enhance the technical development for modeling and magnetic field generation for deep brain penetration such as the circuit topology and coil design. Besides, the stimulation parameters (waveform, pulse duration, stimulation frequency and amplitude) also play an important role in stimulating target cortical area. In this project, a microprocessor-based system for controlling the generation of magnetic field by the TMS device is developed. The TMS electric field intensity, which is proportional to the voltage of the storage capacitor, can be configured quickly using the digital-to-analog (DAC) module. The pulse duration, which is eligible to control the switching device (insulated-gate bipolar transistor IGBT) between the storage capacitor and the induced coil, can be adjusted by the internal timer/counter inside the microprocessor. Furthermore, the designed frequency patterns for specific treatment purposes (rTMS, cTBS, iTBS) are generated by monitoring the previous pulse width frequency. At the moment, the control unit has been tested together with the monophasic TMS device at different energy levels to monitor the artifacts before delivering it to the clinical services. It should be noted that the desinged controlling system is suitable for controlling either single coil or multiple coils TMS device. In the multi-coil TMS, separated coils can be controlled independently or simultaneously which provide the promising application of delivering stimulation pulses in different locations without moving the coils.

1. 融合大鼠显着性网络的结构和功能证据显着网络（SN）在许多神经精神疾病中失调，包括物质使用障碍。最初在人类中进行了描述，对啮齿动物 SN 的识别将提供在神经精神疾病的临床前模型中机械地询问该网络的能力。我们对大鼠 (n=32) 的静息态功能 MRI 数据进行模块化分析，将大鼠岛叶划分为功能分区，并根据岛叶分区的功能连接模式识别潜在的大鼠 SN。然后，我们使用来自艾伦大脑图谱的小鼠脑束追踪数据来确认潜在结构连接的网络。接下来，我们比较了大鼠、狨猴 (n=10) 和人类 (n=30) 的 SN 功能连接概况。最后，我们评估了具有海洛因自我给药史的大鼠 (n=21) 的大鼠 SN 对条件线索的反应。我们根据腹侧前岛叶的功能连接模式，确定了一种假定的大鼠 SN，其主要由腹侧前岛叶和前扣带皮层组成。小鼠神经元示踪数据支持大鼠 SN 的功能连接架构。此外，所鉴定的大鼠 SN 的解剖学特征与非人类灵长类动物和人类相似。最后，我们证明了大鼠 SN 在条件海洛因戒断期间对条件线索做出反应，并增加了与默认模式网络的功能连接。总之，大鼠 SN 的神经生物学鉴定及其功能相关性的证明提供了一个新的平台，可用于探讨其在规范和神经精神疾病模型中的功能意义。（Tsai 等人，《生物精神病学》，待出版） 2. 焦点深部经颅磁刺激线圈的设计传统的经颅磁刺激 (TMS) 线圈受到深度焦点权衡规则的限制。具有小孔径或大孔径的线圈的发射场强度将在距线圈小于一孔径直径的距离处快速发散。为了利用更好的深度-焦点权衡规则并实现深度和集中的刺激，需要采用一种新方法。我们设计了一种新型 TMS 线圈，可以向更深层的大脑区域提供光斑大小可调的刺激。通过将其刺激深度和焦点与其他 50 个线圈进行比较，我们的研究得出结论，所提出的方法打破了深度-焦点权衡规则。理论计算和实验数据共同证明了由线圈导电绕组的调谐角度控制的可调焦点。我们的 TMS 线圈设计在深度焦点轮廓中绘制了一条新曲线，在权衡规则中比所有现有的传统线圈设计具有更好的性能。 3. 清醒大鼠的局灶经颅磁刺激：增强深层皮质层的葡萄糖摄取经颅磁刺激（TMS）是一种新兴的神经调节工具。然而，TMS 的临床前模型有限。该研究的目的是开发一种在清醒大鼠中进行 TMS 的方法，并通过绘制 TMS 给药后的葡萄糖摄取图来表征神经元对 TMS 的反应。将头柱植入大鼠头骨中，作为引导 TMS 目标的参考。运动阈值测量被用作评估跨动物和跨会话 TMS 传递一致性的指标。使用荧光葡萄糖类似物 (2-NBDG) 作为神经元活动的标记，我们绘制了大鼠运动皮层对 TMS 响应的葡萄糖摄取图。我们的结果显示平均运动阈值 (n = 41) 为最大刺激器输出 (MSO) 的 34.6±6.3%。动物运动阈值的变异性与人类研究中报道的相似。此外，三天内测量的运动阈值没有显着差异。荧光信号的增强与 TMS 剂量（功率）相关，以运动皮层为中心，覆盖内侧-外侧 2 毫米的区域，55% MSO 时覆盖头尾 4 毫米，35% MSO 时覆盖 3 毫米。具有显着荧光信号的总细胞计数为：107 23 (55 % MSO)、73 11 (35 % MSO) 和 42 11 (假手术，5% MSO)。总之，我们的方法允许对纵向研究进行一致的运动阈值评估。值得注意的是，具有荧光信号增强的细胞一致聚集在深层皮质层中，而浅层中的增强程度最小。据我们所知，这是首次在清醒啮齿类动物中进行局灶性经颅磁刺激研究。（萨曼莎等人，神经科学方法杂志，2020）。 4. 基于微处理器的经颅磁刺激控制系统经颅磁刺激（TMS）是一种针对特定皮质区域进行脑神经刺激的非侵入性技术。在 TMS 过程中，波形脉冲刺激被发送到放置在受试者头皮上的线圈，其中线圈产生的磁场在大脑皮层中感应出电场。目前，领先的TMS研究致力于加强电路拓扑和线圈设计等深部脑穿透建模和磁场生成的技术开发。此外，刺激参数（波形、脉冲持续时间、刺激频率和幅度）对刺激目标皮层区域也起着重要作用。在该项目中，开发了一种基于微处理器的系统，用于控制 TMS 设备产生磁场。 TMS 电场强度与存储电容器的电压成正比，可以使用数模 (DAC) 模块快速配置。脉冲持续时间可以通过微处理器内部的定时器/计数器来调节，该脉冲持续时间可以控制存储电容器和感应线圈之间的开关器件（绝缘栅双极晶体管IGBT）。此外，用于特定治疗目的的设计频率模式（rTMS、cTBS、iTBS）是通过监测先前的脉冲宽度频率生成的。目前，控制单元已与单相 TMS 设备一起在不同能量级别进行了测试，以在将其交付临床服务之前监控伪影。应当注意的是，所设计的控制系统适用于控制单线圈或多线圈TMS装置。在多线圈 TMS 中，可以独立或同时控制分离的线圈，这提供了在不移动线圈的情况下在不同位置传递刺激脉冲的有前景的应用。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Temporary disruption of the rat blood-brain barrier with a monoclonal antibody: a novel method for dynamic manganese-enhanced MRI.

DOI：
10.1016/j.neuroimage.2009.12.053
发表时间：
2010-03
期刊：
NEUROIMAGE
影响因子：
5.7
作者：
Lu, Hanbing;Demny, Steven;Zuo, Yantao;Rea, William;Wang, Leiming;Chefer, Svetlana I.;Vaupel, D. Bruce;Yang, Yihong;Stein, Elliot A.
通讯作者：
Stein, Elliot A.

Focal transcranial magnetic stimulation in awake rats: Enhanced glucose uptake in deep cortical layers.

DOI：
10.1016/j.jneumeth.2020.108709
发表时间：
2020-06-01
期刊：
Journal of neuroscience methods
影响因子：
3
作者：
Cermak S;Meng Q;Peng K;Baldwin S;Mejías-Aponte CA;Yang Y;Lu H
通讯作者：
Lu H

Functional Connectivity Hubs and Networks in the Awake Marmoset Brain.

醒着的马尔莫斯脑大脑中的功能连接枢纽和网络。

DOI：
10.3389/fnint.2016.00009
发表时间：
2016
期刊：
Frontiers in integrative neuroscience
影响因子：
3.5
作者：
Belcher AM;Yen CC;Notardonato L;Ross TJ;Volkow ND;Yang Y;Stein EA;Silva AC;Tomasi D
通讯作者：
Tomasi D

A novel method to induce nicotine dependence by intermittent drug delivery using osmotic minipumps.