Noninvasive imaging-based electrophysiology using microelectronic devices

描述(申请人提供)：这个项目的目标是建立一种策略，使神经元电信号可以通过磁共振成像(MRI)在全脑水平上进行检测。我们的方法建立在使用细胞黏附微米级电子设备将大脑中的神经元电位转换为磁场波动的新概念上。作为对这些电压敏感微探针验证的一部分，我们还建议实施一种新的、可扩展的方法，用于同时记录MRI和电生理数据。我们建议开发的方法将广泛适用于神经生物学问题，并将改变神经科学家研究大脑综合功能的能力。我们的微探针方法还将有助于在诊断医学和分子成像方面建立一种新的范式，其中微小的机器，而不是传统的化学造影剂，将报告细胞生理的各个方面。最近的工作表明，微米级的电极，涂有细胞黏附分子并与培养的细胞并列，可以记录毫伏级的动作电位，可与细胞内记录相媲美。如果将微电极中感应的电流导入电感，就可以将其转化为适度的瞬变磁场。在具体目标1中，我们将模拟螺旋或螺线管型微线圈中可行电流产生的磁场，计算作为微探针分布的函数对磁共振信号幅度和相位的预测影响，并制造微探针本身。初步计算表明，在直径1.5米的单圈10圈微线圈中可以产生约10nT的局域瞬变场。这个数量级的磁场比在脑磁图等技术中检测到的内源性神经元磁场更大，以前已经证明在某些情况下MRI是可以测量的。在具体目标2中，我们将测试我们的微探针在核磁共振中报告神经元群的动作电位的能力。微型设备将首先应用于培养的神经元或神经组织切片，并放置在核磁共振扫描仪中。将使用多种协议获得数据系列，以检测由于神经元活动的变化而导致的MRI信号的变化。如果培养实验成功，微探针将被定点注射到麻醉大鼠的大脑皮层，并在体感刺激范式中进行测试。在具体目标3中，我们将建立一种同时进行MRI和常规电生理学的方法来直接验证新的MRI电压探针。在MRI扫描仪中执行电生理学因扫描硬件引起的伪影而变得复杂，特别是由于切换的梯度场。为了避免这个问题，我们将使用四极管或改良四极管上的通道对的差异记录来测量神经元电位。一旦改进了扫描仪记录方法，将获得基于MRI的电生理数据并将其与传统电生理学数据进行比较，以评估电压敏感微探头的性能，并在必要时指导进一步改进。

DESCRIPTION (provided by applicant): The goal of this project is to establish a strategy that will make neuronal electrical signaling detectable via magnetic resonance imaging (MRI) at a whole-brain level. Our approach is built on the novel concept of using cell-adhesive micron-scale electronic devices to transduce neuronal potentials across the brain into magnetic field fluctuations. As part of our validation of these voltage-sensing microprobes, we also propose to implement a new, scalable method for simultaneous recording of MRI and electrophysiological data. The methods we propose to develop will be broadly applicable to problems in neurobiology, and will transform neuroscientists' ability to study integrative functions of the brain. Our microprobe approach will also help establish a new paradigm in diagnostic medicine and molecular imaging, where tiny machines, rather than conventional chemical contrast agents, will report on aspects of cellular physiology. Recent work has dem- onstrated that micron-scale electrodes, coated with cell-adhesive molecules and juxtaposed against cultured cells allow recording of millivolt-scale action potentials, comparable to intracellular recordings. The current induced in a microelectrode can be converted into a modest, transient magnetic field if it is channeled into an inductor. In Specific Aim 1, we will model the magnetic fields produced by feasible currents in spiral or solenoidal microcoils of defined geometry, compute predicted effects on MRI signal amplitude and phase as a function of microprobe distribution, and fabricate the microprobes themselves. Preliminary calculations indicate that localized, transient fields of about 10 nT could be produced in individual 10-turn microcoils of 1 5m diameter. Magnetic fields of this order are greater than endogenous neuronal fields detected in tech- nologies like magnetoencephalography, and have been shown previously to be measurable by MRI in some contexts. In Specific Aim 2, we will test the ability of our microprobes to report action potentials from neu- ronal populations in MRI. The microdevices wil first be applied to cultured neurons or neural tissue slices and placed in an MRI scanner. Data series will be obtained using multiple protocols to detect variations of MRI signal due to variations in neuronal activity. If experiments in culture are successful, microprobes will be site-specifically injected into the cerebral cortex of anesthetized rats, and tested in an somatosensory stimu- lation paradigm. In Specific Aim 3, we will establish a simultaneous MRI and conventional electrophysiology approach to validate the novel MRI voltage probes directly. Performing electrophysiology in an MRI scanner is complicated by artifacts induced by the scanning hardware, in particular due to switched gradient fields. To circumvent this problem, we will measure neuronal potentials using differential recording from pairs of channels on tetrodes or modified tetrodes. Once the in-scanner recording method has been refined, MRI- based and conventional electrophysiology data will be obtained and compared to assess performance of the voltage-sensing microprobes, and to guide further improvements, if necessary.