Noninvasive imaging-based electrophysiology using microelectronic devices

描述（由申请人提供）：本项目的目标是建立一种策略，通过磁共振成像（MRI）在全脑水平检测神经元电信号。我们的方法是建立在使用细胞粘附的微米级电子设备的新概念，以将整个大脑的神经元电位转换为磁场波动。作为我们验证这些电压传感微探针的一部分，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。我们提出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领域建立一个新的范式，在这种范式中，微型机器，而不是传统的化学造影剂，将报告细胞生理学的各个方面。最近的工作已经证明，涂覆有细胞粘附分子并与培养细胞并列的微米级电极允许记录毫伏级动作电位，与细胞内记录相当。微电极中感应的电流如果被引导到电感器中，则可以被转换成适度的瞬态磁场。在具体目标1中，我们将对定义几何形状的螺旋或螺线管微线圈中的可行电流产生的磁场进行建模，计算对MRI信号幅度和相位的预测影响，作为微探针分布的函数，并制造微探针本身。初步计算表明，局部的，瞬态场约10 nT可以产生在个别10圈微线圈的直径为15米。这种量级的磁场大于在脑磁图等技术中检测到的内源性神经元场，并且先前已经证明在某些情况下可以通过MRI测量。在特定目标2中，我们将测试我们的微探针在MRI中报告神经元群体动作电位的能力。这种微型装置将首先应用于培养的神经元或神经组织切片，并置于MRI扫描仪中。将使用多个方案获得数据系列，以检测由于神经元活动变化而导致的MRI信号变化。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，并在体感刺激范例中进行测试。在特定目标3中，我们将建立一种同步MRI和常规电生理方法，以直接验证新型MRI电压探头。在MRI扫描仪中执行电生理学是由扫描硬件引起的伪影（特别是由于切换的梯度场引起的伪影）而复杂化的。为了避免这个问题，我们将使用差分记录从四极或修改的四极上的通道对测量神经元电位。一旦完善了扫描仪内记录方法，将获得基于MRI的和传统的电生理数据，并进行比较，以评估电压传感微探针的性能，并指导进一步的改进（如有必要）。

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.