Microelectrode arrays and microprobes have been widely utilized to measure neuronal activity, both in vitro and in vivo. The key advantage is the capability to record and stimulate neurons at multiple sites simultaneously. However, unlike the single-cell or single-channel resolution of intracellular recording, microelectrodes detect signals from all possible sources around every sensor. Here, we review the current understanding of microelectrode signals and the techniques for analyzing them. We introduce the ongoing advancements in microelectrode technology, with focus on achieving higher resolution and quality of recordings by means of monolithic integration with on-chip circuitry. We show how recent advanced microelectrode array measurement methods facilitate the understanding of single neurons as well as network function.

Axons are traditionally considered stable transmission cables, but evidence of the regulation of action potential propagation demonstrates that axons may have more important roles. However, their small diameters render intracellular recordings challenging, and low-magnitude extracellular signals are difficult to detect and assign. Better experimental access to axonal function would help to advance this field. Here we report methods to electrically visualize action potential propagation and network topology in cortical neurons grown over custom arrays, which contain 11,011 microelectrodes and are fabricated using complementary metal oxide semiconductor technology. Any neuron lying on the array can be recorded at high spatio-temporal resolution, and simultaneously precisely stimulated with little artifact. We find substantial velocity differences occurring locally within single axons, suggesting that the temporal control of a neuron's output may contribute to neuronal information processing.

Studies on information processing and learning properties of neuronal networks would benefit from simultaneous and parallel access to the activity of a large fraction of all neurons in such networks. Here, we present a CMOS-based device, capable of simultaneously recording the electrical activity of over a thousand cells in in vitro neuronal networks. The device provides sufficiently high spatiotemporal resolution to enable, at the same time, access to neuronal preparations on subcellular, cellular, and network level. The key feature is a rapidly reconfigurable array of 26 400 microelectrodes arranged at low pitch (17.5 μm) within a large overall sensing area (3.85 × 2.10 mm(2)). An arbitrary subset of the electrodes can be simultaneously connected to 1024 low-noise readout channels as well as 32 stimulation units. Each electrode or electrode subset can be used to electrically stimulate or record the signals of virtually any neuron on the array. We demonstrate the applicability and potential of this device for various different experimental paradigms: large-scale recordings from whole networks of neurons as well as investigations of axonal properties of individual neurons.

No abstract

To advance our understanding of the functioning of neuronal ensembles, systems are needed to enable simultaneous recording from a large number of individual neurons at high spatiotemporal resolution and good signal-to-noise ratio. Moreover, stimulation capability is highly desirable for investigating, for example, plasticity and learning processes. Here, we present a microelectrode array (MEA) system on a single CMOS die for in vitro recording and stimulation. The system incorporates 26,400 platinum electrodes, fabricated by in-house post-processing, over a large sensing area (3.85 × 2.10 mm 2 ) with sub-cellular spatial resolution (pitch of 17.5 μm). Owing to an area and power efficient implementation, we were able to integrate 1024 readout channels on chip to record extracellular signals from a user-specified selection of electrodes. These channels feature noise values of 2.4 μV rms in the action-potential band (300 Hz-10 kHz) and 5.4 μV rms in the local-field-potential band (1 Hz-300 Hz), and provide programmable gain (up to 78 dB) to accommodate various biological preparations. Amplified and filtered signals are digitized by 10 bit parallel single-slope ADCs at 20 kSamples/s. The system also includes 32 stimulation units, which can elicit neural spikes through either current or voltage pulses. The chip consumes only 75 mW in total, which obviates the need of active cooling even for sensitive cell cultures. I IntroductionEXTRACELLULAR RECORDINGS of the electrical activity of neural and cardiac cell networks in organs such as the brain, the retina, or the heart, can provide a wealth of information about the physiology as well as the pathological degenerations that may cause diseases, such as Parkinson's or Alzheimer's. Microelectrode arrays (MEAs) have been used for a long time for in vitro extracellular recordings of electrogenic cell cultures and tissues, such as acute or organotypic brain slices and retinae [1]- [3]. They provide simultaneous multisite recording capability, which is essential to study cellular interconnections and network properties that arise from synchronized cellular activity [4], [5]. However, passive MEAs, which typically include metal electrodes on a glass substrate, are limited in both the number of electrodes (usually less than 300) and the spatial resolution (typically ≥ 30 μm),features that are needed to reconstruct large neural networks at cellular detail.With CMOS technology, these limitations can be overcome by using multiplexing techniques, which enable access to a large number of closely-spaced electrodes to obtain large sensing areas at high spatial resolution [6]. Moreover, the monolithic integration of recording amplifiers and ADCs, on the same substrate with the electrodes, avoids off-chip parasitics and interference and, at the same time, allows for realizing a large number of recording channels with a low number of connections. In this paper, we present a recently developed CMOS MEA system that further exploits the switch-matrix approach. The system preserves s...

No abstract

Advances in microfabrication technology have enabled the production of devices containing arrays of thousands of closely spaced recording electrodes, which afford subcellular resolution of electrical signals in neurons and neuronal networks. Rationalizing the electrode size and configuration in such arrays demands consideration of application-specific requirements and inherent features of the electrodes. Tradeoffs among size, spatial density, sensitivity, noise, attenuation, and other factors are inevitable. Although recording extracellular signals from neurons with planar metal electrodes is fairly well established, the effects of the electrode characteristics on the quality and utility of recorded signals, especially for small, densely packed electrodes, have yet to be fully characterized. Here, we present a combined experimental and computational approach to elucidating how electrode size, and size-dependent parameters, such as impedance, baseline noise, and transmission characteristics, influence recorded neuronal signals. Using arrays containing platinum electrodes of different sizes, we experimentally evaluated the electrode performance in the recording of local field potentials (LFPs) and extracellular action potentials (EAPs) from the following cell preparations: acute brain slices, dissociated cell cultures, and organotypic slice cultures. Moreover, we simulated the potential spatial decay of point-current sources to investigate signal averaging using known signal sources. We demonstrated that the noise and signal attenuation depend more on the electrode impedance than on electrode size, per se , especially for electrodes <10 μm in width or diameter to achieve high-spatial-resolution readout. By minimizing electrode impedance of small electrodes (<10 μm) via surface modification, we could maximize the signal-to-noise ratio to electrically visualize the propagation of axonal EAPs and to isolate single-unit spikes. Due to the large amplitude of LFP signals, recording quality was high and nearly independent of electrode size. These findings should be of value in configuring in vitro and in vivo microelectrode arrays for extracellular recordings with high spatial resolution in various applications.

No abstract