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

描述 摘要： 尽管在描述单个神经元的特性方面已经取得了很大的进展，但在我们理解数十亿个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。显然，阻碍系统神经科学进步的最大障碍是很难在自由行为的动物身上观察到大量神经元的活动。以动作电位和突触电流的形式流动的电流是大脑的通货，神经活动和突触变化对毫秒级的时间尺度很敏感。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级分辨率的电活动。然而，最先进的多电极阵列有大约100个记录点，因此只能非常稀疏地采样神经元活动。这种限制使得我们很难推断出任何有关全球大脑模式及其随时间演变的信息。为了克服这些限制，我们建议开发纳米探针阵列，在大幅提高其空间分辨率和规模的同时，保持电生理学的特殊时间分辨率。拟议中的阵列将拥有数万个记录地点--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的大脑活动图，揭示出远远超出当前技术能力的基本规律。这一发展将推动多个层面的创新：探测器的设计和纳米制造、与有源电子设备的集成、高速采集系统的开发、用于在动物身上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据 通过使用基于铸造的概念原型来实现广泛可用的变革性研究工具 能够以最高水平的质量和再现性进行大规模生产的制造。其中约有 探头内记录位置之间的20μm间距--大致相当于单个神经元的大小--以及足够大的 每个探头的位置数量，将不再需要微调电极的位置以隔离 单个神经元的活动。这将是一个关键的进步，为高吞吐量打开了大门 在自由行为的动物中的电生理学，并将使创建巨大的 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分析之间的差距 对制药和生物技术行业的变革性影响。纳米探针阵列也将 在神经外科和脑机接口方面有高影响力的应用，如高分辨率 癫痫灶的定位和可利用更丰富曲目的假体装置的开发 比目前可能的活动模式更多。

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.