Noninvasive imaging-based electrophysiology using microelectronic devices

描述（由申请人提供）：该项目的目标是建立一种策略，通过磁共振成像（MRI）在全脑水平上检测神经元电信号。我们的方法是建立在使用细胞粘附的微米级电子设备将整个大脑的神经元电位转换为磁场波动的新概念之上。作为我们对这些电压传感微探针验证的一部分，我们还建议实现一种新的，可扩展的方法来同时记录MRI和电生理数据。我们提出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。我们的微探针方法也将有助于在诊断医学和分子成像中建立一个新的范例，在那里，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，微米级的电极，涂有细胞粘附分子，并与培养的细胞并列，可以记录毫伏级的动作电位，与细胞内记录相当。在微电极中产生的电流如果被引入电感器，就可以转化为适度的瞬态磁场。在具体目标1中，我们将在定义几何形状的螺旋或螺线形微线圈中模拟可行电流产生的磁场，计算微探针分布对MRI信号幅度和相位的预测影响，并制作微探针本身。初步计算表明，单个直径为1 5m的10匝微线圈可以产生约10 nT的局部瞬态场。这种量级的磁场比脑磁图等技术检测到的内源性神经元磁场更大，并且在某些情况下已经证明可以通过MRI测量。在具体目标2中，我们将测试我们的微探针在MRI中报告来自新区域群体的动作电位的能力。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，并置于核磁共振扫描仪中。数据序列将使用多种方案来检测由于神经元活动的变化而引起的MRI信号的变化。如果培养实验成功，微探针将被特定部位注射到麻醉大鼠的大脑皮层中，并在体感刺激范式中进行测试。在具体目标3中，我们将建立同时MRI和传统电生理学方法来直接验证新型MRI电压探头。在MRI扫描仪中执行电生理是复杂的，由扫描硬件引起的伪影，特别是由于切换梯度场。为了避免这个问题，我们将使用四极体或改良四极体上通道对的差分记录来测量神经元电位。一旦扫描仪内记录方法得到改进，将获得基于MRI和传统电生理数据，并对其进行比较，以评估电压传感微探针的性能，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.