Nanoprobe arrays for massively parallel 3-D recordings of brain activity

描述 摘要： 虽然在表征单个神经元的特性方面已经取得了很大的进步，但在我们理解数十亿神经元如何协同工作以产生感知，学习和记忆等复杂现象之前，仍然存在巨大的挑战。迄今为止，系统神经科学进步的最大障碍是难以观察自由行为动物中大量神经元的活动。以动作电位和突触电流形式的电流是大脑的流通，神经活动和突触变化对毫秒级的时间尺度敏感。因此，电生理学一直是监测大脑的黄金标准，因为它直接测量亚毫秒分辨率的电活动。然而，现有技术的多电极阵列具有大约100个记录位点，因此只能非常稀疏地对神经元活动进行采样。这种限制使得我们很难推断出全球大脑模式及其随时间的演变。为了克服这些限制，我们建议开发纳米探针阵列，它保留了电生理学的特殊时间分辨率，同时大大提高了空间分辨率和规模。拟议中的阵列将有数万个记录点比目前的设备高出两个数量级，并将能够以前所未有的时空分辨率绘制整个脑组织体积的大脑活动，揭示远远超出当前技术范围的基础知识。这一发展将在许多层面上推动创新：探针的设计和纳米制造，与有源电子器件的集成，高速采集系统的开发，用于在行为动物中进行广泛测试的植入式接口，以及计算和分析基础设施的开发。我们的目标是超越证明 通过采用基于铸造的概念原型， 制造，使大规模生产的质量和再现性的最高水平。约 探针内记录点之间的间距为20 μm--大约是单个神经元的大小--以及足够大的 每个探头的位点数量，将不再需要微调电极的定位以隔离 单个神经元的活动。这将是一个关键的进步，打开大门，高通量 电生理学在自由行为的动物，并将使建立巨大的图书馆， 跨大脑区域的时空模式-基因组的电生理模拟。测试 药物对这些模式的影响将弥合分子和行为测定之间的差距， 对制药和生物技术行业的变革性影响。纳米探针阵列还将 在神经外科和脑机接口中具有高影响力的应用，例如高分辨率 癫痫灶的定位和假体装置的开发，可以利用更丰富的剧目 比目前可能的活动模式。

DESCRIPTION Abstract: Although great strides have been made in characterizing the properties of single neurons, enormous challenges remain before we understand how billions of neurons work in concert to produce complex phenomena such as perception, learning, and memory. Far and away, the biggest obstacle towards progress in systems neuroscience has been the difficulty of observing the activity of large populations of neurons in freely behaving animals. The flow of electricity in the form of action potentials and synaptic currents is the currency of the brain, and neural activity and synaptic changes are sensitive to millisecond timescales. Hence electrophysiology has been the gold standard for monitoring the brain since it directly measures electrical activity with sub-millisecond resolution. However, state of the art multi-electrode arrays have about 100 recording sites and can thus sample neuronal activity only very sparsely. This constraint makes it difficult to infer anything about global brain patterns and their evolution in time. To overcome these limitations, we propose to develop nanoprobe arrays which preserve the exceptional temporal resolution of electrophysiology while drastically increasing its spatial resolution and scale. The proposed arrays will have tens of thousands of recording sites-two orders of magnitude higher than current devices-and will enable mapping brain activity across entire volumes of brain tissue with unprecedented spatiotemporal resolution, exposing fundamental regularities far beyond the reach of current technologies. This development will fuel innovations at many levels: the design and nanofabrication of probes, integration with active electronics, development of high-speed acquisition systems, implantable interfaces for extensive testing in behaving animals, and development of computational and analysis infrastructure. Our goal is to go beyond proof of concept prototypes towards widely available transformative research tools by employing foundry-based fabrication that enables mass production at the highest levels of quality and reproducibility. With approximately 20 μm spacing between recording sites within a probe–roughly the size of a single neuron–and a large enough number of sites per probe, it will no longer be necessary to fine-tune the positioning of electrodes to isolate the activity of individual neurons. This will be a pivotal advance that opens the door to high-throughput electrophysiology in freely behaving animals and will enable the creation of enormous libraries of spatiotemporal patterns across brain areas–an electrophysiological analogue of the genome. Testing the effects of drugs on these patterns will bridge the gap between molecular and behavioral assays with transformative implications for the pharmaceutical and biotechnology industries. Nanoprobe arrays will also have high-impact applications in neurosurgery and brain-machine interfaces, such as the high-resolution localization of epileptic foci and the development of prosthetic devices that can exploit a much richer repertoire of activity patterns than currently possible.