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。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（包括药物使用障碍）中失调。最初在人类中描述的是，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询问该网络的能力。我们对大鼠的静息状态功能MRI数据（n = 32）使用模块化分析，以将大鼠岛裂成功能细分，并基于Insular Subdivisions的功能连接模式识别潜在的大鼠SN。然后，我们使用了来自Allen Brain Atlas的鼠标追踪数据来确认结构连接性的网络。接下来，我们比较了SN跨大鼠，Marmoset（n = 10）和人类（n = 30）的功能连通性曲线。最后，我们评估了大鼠对大鼠（n = 21）中有条件提示的反应，并具有海洛因自我管理史。我们确定了一个假定的大鼠SN，该大鼠SN主要由腹侧前缘和前扣带回皮层组成，该sn基于腹侧前岛隔离的功能连通性模式。大鼠SN的功能连通性结构由小鼠神经元示踪剂数据支持。此外，已鉴定的大鼠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对条件提示的响应，并增加了有条件的海洛因提取期间与默认模式网络的功能连接。总之，对大鼠SN的神经生物学识别以及其功能相关性的演示提供了一个新的平台，可以通过该平台询问其在规范性和神经精神病模型中的功能意义。（Tsai等人，生物精神病学，印刷中） 2。局灶性深颅磁刺激线圈的设计常规的经颅磁刺激（TMS）线圈受到深度焦点权衡规则的限制。来自小孔或大孔的线圈的发射场强度将在距线圈直径距离不到一个孔径距离的情况下迅速差异。要利用更好的深度焦点权衡规则并实现深入而集中的刺激，需要采用一种新的方法。我们设计了一种新型的TMS线圈，可以为更深的大脑区域提供可调节斑点的刺激。通过将其刺激深度和焦点与其他50个线圈进行比较，我们的研究得出了拟议的方法，即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控制的可调节焦点。我们的TMS线圈设计将一个新曲线绘制在深度焦点曲线中的新曲线，其性能比权衡规则中现有的所有常规线圈设计更好。 3。清醒大鼠中的局灶性经颅磁刺激：深层皮质层的葡萄糖吸收增强经颅磁刺激（TMS）是一种新兴的神经调节工具。但是，TMS的临床前模型受到限制。该研究的目的是开发一种在醒着大鼠中执行TMS的方法，并通过在TMS给药后绘制葡萄糖摄取来表征对TMS的神经元反应。将头杆植入大鼠头骨中，以重新指导TMS目标。运动阈值测量被用作评估跨动物和跨疗程的TMS递送的一致性的度量。使用荧光葡萄糖模拟（2-NBDG）作为神经元活性的标记，我们响应大鼠运动皮质的TMS绘制了葡萄糖摄取。我们的结果表明，平均运动阈值（n = 41）为最大刺激器输出（MSO）的34.6 6.3％。整个动物的运动阈值的变化与人类研究中报道的相似。此外，在3天之间测得的运动阈值没有显着差异。荧光信号的增强是TMS剂量（功率）依赖性，其围绕运动皮层，覆盖在55％MSO的内侧2 mm内侧2 mm的区域4 mm和35％MSO的3 mm。具有明显荧光信号的总细胞的计数为：107 23（55％MSO），73 11（35％MSO）和42 11（假，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在深层皮质层中始终汇总，在表层层中的增强最小。据我们所知，这是对清醒啮齿动物中焦点TM的首次研究。（Samantha等人，J。Neurosci方法，2020年）。 4。基于微处理器的控制系统，用于经颅磁刺激经颅磁刺激（TMS）是在特定皮质区域的脑神经刺激的非侵入性技术。在TMS期间，将波形脉冲刺激发送到放置在受试者头皮上的线圈，其中线圈产生的磁场诱导了脑皮质中的电场。目前，领先的TMS研究旨在增强用于建模和磁场生成的技术开发，以进行深度大脑渗透，例如电路拓扑和线圈设计。此外，刺激参数（波形，脉冲持续时间，刺激频率和振幅）在刺激目标皮质区域也起着重要作用。在此项目中，开发了用于控制TMS设备生成磁场的微处理器系统。与存储电容器电压成正比的TMS电场强度可以使用数字到Analog（DAC）模块快速配置。脉冲持续时间有资格控制存储电容器和诱导的线圈之间的开关装置（绝缘栅极双极晶体管IGBT），可以通过微处理器内部的内部计时器/计数器进行调整。此外，通过监视先前的脉冲宽度频率来生成设计用于特定治疗目的的设计频率模式（RTMS，CTB，ITB）。目前，控制单元已与单相TMS设备在不同能量水平上进行了测试，以在将其传递给临床服务之前监测伪像。应该注意的是，底线的控制系统适合控制单线圈或多个线圈TMS设备。在多线圈TMS中，可以独立或同时控制分离的线圈，从而提供有希望的应用在不同位置传递刺激脉冲而无需移动线圈的应用。

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.

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.