Capabilities of MRI-Based Neural Current Imaging for Human Brain Mapping

 描述(由申请人提供)：在这项提案中，我们利用我们在MRI采集方法和新的动物模型方面的最新发展，尝试使用磁共振成像(MRI)直接检测神经元电流。如果成功，该项目将对神经系统的科学研究产生重大影响，通过补充常用的基于血流动力学的MR血氧水平依赖(BOLD)功能磁共振成像(FMRI)技术，形成人类神经科学的强大新工具。虽然功能磁共振成像是人类神经科学的主要工具，但它有严重的缺陷，主要是由于神经元活动(电生理学)和血流动力学反应之间的复杂耦合。尽管这两者是相关的，但很明显，当通过“血液动力学过滤器”查看时，信息会丢失。简而言之，我们寻求一种真正的基于MR的“非侵入性电生理学”。其他非侵入性成像手段，如脑磁图(MEG)和脑电图(EEG)，确实可以直接测量突触后电流产生的电场和磁场形式的神经元活动。虽然临床和研究工具得到了验证，但它们也有局限性。因为它们探测到头部外部的磁场，所以它们只对具有特定突触后总电流分布的大群神经元一致放电才敏感。例如，MEG对相对于球形头部径向定向的电流不敏感。电流来自垂直于皮质表面的锥体细胞，非径向约束导致皮质以放射状方向折叠的多个“盲点”。EEG也有类似的问题。最后，这两种模式都共享有限的空间分辨率，并且存在一个“不适定的逆问题”，这使得在不假设震源的性质和分布的情况下确定震源位置是不可能的。净效应是一种可以直接获得时间动态的方式，但与MRI相比，成像能力有限。在这个提案中，我们概述了一个研究项目，该项目追求一种新的MRI技术来直接检测神经元电流。它的成功开发将绕过脑磁图和脑电的许多问题，通过探测每个MRI体素中的局部神经元磁场，从而提供高空间分辨率，而不会出现血流动力学过滤器的并发症。在过去的15年里，人们进行了许多使用MRI的尝试，但都没有明显的成功。我们提出了一种基于自旋锁定磁共振序列(刺激诱导旋转饱和：SIRS)与以10-100赫兹振荡的磁场共振相互作用的新的磁共振方法。与其他需要不真实的直流场的MR检测方法相比，对振荡场的敏感性是一个显著的改进。虽然我们已经证明，该序列的最低检测阈值与以前的方法一样低，但它仍然是一个探索性的建议，将受益于协调一致的努力和强大的、容易控制的刺激。因此，我们计划使用我们之前用于功能磁共振的光遗传大鼠模型来测试我们的方法。在这项准备中，将体感皮质中的神经元导入表达通道视紫红质-2(ChR2)通道，该通道在光照时兴奋神经元。我们发现，光刺激产生与受控光刺激同步的极强电生理神经信号。光遗传模型是MR兼容的，允许毫秒级的激活控制，并与其他刺激相比，引起神经元放电的强烈一致性。我们建议采用精心控制的动物实验进行重点研究，以避免标准血流动力学信号的污染。例如，利用电生理学和功能磁共振成像，我们证明了在大鼠模型中，通过吸入二氧化碳(CO2/O2)可以完全消除伴随的BOLD激活。作为这项提议的中心焦点，SIRS将被实施并用于检测ChR2基因转基因大鼠模型中的神经电信号。将特别注意去除混杂因素，如血液动力学MRI信号，结合独立的电生理学，以验证光遗传学诱导的神经活动的特征。这个为期两年的项目的输出将是一个经过验证的MRI方法，然后可以用来量化和空间映射电生理活动。目的1：优化光基因修饰大鼠的Carbogen(5%CO2/95%O2)剂量，以消除BOLD激活，同时保持神经电活动对光遗传刺激的反应。我们假设：吸入Carbogen可以消除光遗传刺激引起的BOLD激活；吸入Carbogen不会影响光遗传刺激引起的电生理活动。目的2：通过长时间阻断实验捕捉神经元电流效应，将刺激诱导旋转饱和(SIRS)获得应用于视神经修饰大鼠。我们假设：在全身性高氧/高二氧化碳状态下，光遗传刺激产生基于SIRS的MRI信号；光刺激的幅度与神经活动成正比； 频率不匹配的刺激不会产生基于SIRS的神经信号。

 DESCRIPTION (provided by applicant): In this proposal we leverage our recent developments in MRI acquisition methods and new animal models to attempt direct detection of neuronal currents with Magnetic Resonance Imaging (MRI). If successful, this project will have a high impact for scientific investigations of the nervous system, forming a powerful new tool for human neuroscience by supplementing the commonly applied hemodynamic based MR blood oxygenation level dependent (BOLD) functional MRI (fMRI) technique. Although fMRI is a primary tool for human neuroscience, it has severe shortcomings primarily arising from the complex coupling between neuronal activity (electrophysiology) and the hemodynamic response. Although the two are correlated, it is clear that information is lost when viewed through the "hemodynamic filter." In short, we seek a true MR based "non-invasive electrophysiology." Other non-invasive imaging modalities such as Magnetoencephalography (MEG) and Electroencephalography (EEG) do directly measure the neuronal activity in the form of the electric and magnetic fields produced by post-synaptic currents. While proven clinical and research tools, they also have limitations. Because they detect the field outside the head, they are sensitive only to large groups of neurons firing coherently with certain total post-synaptic current distributions. For example MEG is not sensitive to currents oriented radially with respect to the spherical head. The currents derive from pyramidal cells oriented normal to the cortical surface and the non-radial constraint causes multiple "blind spots" where the cortex folds in such a way that the pyramidal cells are oriented radially. EEG shares a similar problem. Finally, both modalities share limited spatial resolution complicated by an "ill posed inverse problem" which makes it impossible to determine the source locations without assumptions about their nature and distribution. The net effect is a modality with direct access to the temporal dynamics, but limited imaging ability compared to MRI. In this proposal, we outline a research project that pursues a novel MRI technique for the direct detection of neuronal currents. Its successful development would bypass many of the problems of MEG and EEG by probing the neuronal magnetic fields locally within each MRI voxel thus providing the high spatial resolution without the complications of the hemodynamic filter. Many attempts using MRI have been pursued over the last 15 years without clear success. We propose a new MR method based on the ability of a spin- lock MRI sequence (stimulus-induced rotary saturation: SIRS) to interact resonantly with magnetic fields oscillating at 10-100Hz. The sensitivity to oscillating fields is a significant improvement over other MR detection methods which require un-realistic DC fields. While we have shown that the sequence's minimum detection threshold is as low as the previous methods, it is nevertheless an exploratory proposal that will benefit from a concerted effort and a strong, readily controllable stimulus. Thus, we plan to test our method using an optogenetic rat model we have previously used for fMRI. In this preparation, neurons in somatosensory cortex are transfected to express ChannelRhodopsin-2 (ChR2) channels that excite neurons when illuminated. We show that optical stimulation produces extremely strong electrophysiological neural signals in synchrony with controlled optical stimuli. The optogenetic model is MR compatible allows millisecond control of the activation and elicits strong coherence of the neuronal firing compared to other stimuli. We propose a focused investigation using carefully controlled animal experiments to avoid contamination with the standard hemodynamic signal. For example, using both electrophysiology and fMRI, we demonstrated that the complete elimination of concomitant BOLD activation can be achieved via carbogen inhalation (CO2/O2) in rat models. As a central focus of this proposal, SIRS will be implemented and used to detect neuroelectric signals in the rat models transfected with ChR2 genes. Particular attention will be paid to remove confounders such as hemodynamic MRI signals in conjunction with independent electrophysiology to verify the characteristics of neural activities induced by optogenetics. The output of this 2 year project will be a validated MRI method that can then be used to quantify and spatially map the electrophysiological activity. Aim 1: Optimize carbogen (5% CO2/ 95% O2) dose in optogenetically modified rats to eliminate BOLD activation while maintaining the neuroelectric activity in response to optogenetic stimuli. We hypothesize that: Inhalation of carbogen removes the BOLD activation induced by optogenetic stimuli; Inhalation of carbogen does not affect the electrophysiological activity induced by optogenetic stimuli. Aim 2: Application of the Stimulus Induced Rotary Saturation (SIRS) acquisition to optogentically modified rats using long block duration experiments capturing neuronal current effects. We hypothesize that: During systemic hyperoxia/hypercapnia, optogenetic stimuli produce SIRS-based MRI signal; The optical stimulation amplitude is proportional to the neural activity; Optical stimulation with unmatched frequency does not result in SIRS-based neural signal.