The effect of optical stimulation of neural tissue is considered in capacitively coupled CMOS micro-electrode arrays used for in vitro extracellular recording from neural tissue. Using a 25-nm high-k TiO2 sensor dielectric with 20% ZrO2, light-induced currents through the dielectric are found at short wavelengths within the visible and relevant spectrum for the above-mentioned purpose. Purely capacitive behavior is obtained for green light and longer wavelength, leakage-induced artifacts at shorter wavelengths are avoided by using optimized operating conditions of recording sites and entire system.

Electrical imaging of extracellular potentials reveals the activity of electrogenic cells and of networks thereof over several orders of magnitude, both in space and time. On a spatial scale, electrical activity propagates in nanometer-sized nerve fibers (axons, dendrites), which connect cells in a biological network over several millimeters. On a temporal scale, changes of the extracellular potential caused by action potentials occur on a sub-millisecond scale, while network activity may be modulated over seconds. Here, different electrode arrays are described, which are designed to image modulations of the electrical potentials over a wide spatiotemporal range. In the second part, typical applications and scientific questions in neuroscience research addressed so far are reviewed. The review ends with an outlook on expected developments.

Event Abstract Back to Event Wavelength-sensitivity of mouse retinal ganglion cells recorded by a high-density micro electrode array (MEA) Florian Jetter1, Gabriel Bertotti2, Roland Thewes3 and Günther Zeck4* 1 NMI at the University Tuebingen, Neurochip Research, Germany 2 Technische Universität Berlin, Chair of Sensor and Actuator Systems, Germany 3 Technische Universität Berlin, Chair of Sensor and Actuator Systems, Germany 4 NMI at the University Tuebingen, Neurochip Research, Germany Motivation: High-density CMOS-MEAs can be used to simultaneously record the electrical spiking activity from hundreds of neurons [Bertotti et al., 2014]. Neuronal spiking can be induced by electrical stimulation [Eickenscheidt and Zeck 2014], by light stimulation applied to a light-sensitive retina [Zeck et al. 2011], or by light stimulation of optogenetically transfected neurons [Herrmann et al. 2014]. In this work, we investigate the wavelength-sensitivity of different mouse retinal ganglion cells and the intrinsic wavelength-sensitivity of the response of high-density CMOS-MEAs. Material and Methods: A CMOS-based high-density MEA comprising 4225 recording sites is used for recording the ganglion cell activity in C57/Bl6 mouse retina during flickering light stimulation (1 and 5 Hz, respectively) with different wavelength and of different light stimulus sizes. Light stimuli presented on a DMD (µ-matrix, Rapp Optoelectronic, Germany) are focused through a microscope objective on the retina. The DMD is illuminated by an LED system commonly used for optogenetic activation (pe-4000, coolLED, UK). Here the results for four stimulation wavelengths are presented (405, 470, 525, and 635nm) at intensities as high as 2 mW/mm² (470 nm). Recorded data is sampled at 25 kHz. Results: Light stimulation (stimulus area: 1 mm2) evokes spiking in the interfaced retina. Based on the stimulus polarity retinal ganglion cells are broadly classified in ON or OFF type, depending on whether they respond to light on- or offset, respectively. In Fig. 1A filtered recordings are shown of the measured extracellular voltage from two selected sensors during 1 Hz stimulation. Both, ON and OFF cell types respond to the three highest wavelengths used here. The sensor site recording the ON transient cell also detects activity from a second OFF cell with smaller amplitude. In Fig.1B we present the unfiltered extracellular voltage traces recorded by a third selected sensor site for all four wavelengths. Light onset leads to a measurable change of the current in the sensing transistor (cf. Bertotti et al., 2014) or more generally speaking of the sensed recording site response, reflected as a low-frequency change of signal back-converted into the voltage domain. However, this does not prevent the detection of light-induced spiking. We note, that the ganglion cell shown in Fig. 1B is not activated by the 635 nm light stimulus. Ongoing experiments investigate the sensitivity of retinal ganglion cells to chromatic stimulation and to stimuli presented at various intensities. The induced variations of the sensor signals are wavelength-dependent, with the highest change obtained for the lowest wavelength (405 nm) and undetectable changes for red light (635 nm). Conclusion: It is shown that recording of cellular spiking activity with CMOS-based MEAs is possible during optical stimulation. Ganglion cells in the mouse retina have different wavelength-sensitivities. The light-induced low-frequency drift of the sensor signals can be completely removed for the tested wavelengths and intensities using high-pass filtering. References: [1] Bertotti G. et al., Proc. IEEE BioCAS, 2014, DOI: 10.1109/BioCAS.2014.6981723 [2] Eickenscheidt M. and Zeck G., J.Neural Eng. 2014, 11(3):036006, DOI:10.1088/1741-2560/11/3/036006 [3] Zeck G. et al., PLoS One, 2011, 6(6):e20810, DOI: 10.1371/journal.pone.0020810 [4] Herrmann T. et al., 2014, Proc. of the 9th Int. Meeting on Substrate-Integrated Microelectrodes, Reutlingen, Germany Figure legend: Light-stimulated ganglion cell activity from mouse retina recorded at four different wavelengths. White segments illustrate time intervals of illumination while grey segments resemble intervals without illumination. (A):Light induced spiking in an OFF sustained ganglion cell type and an ON transient ganglion cell to the same stimulus. The stimulus wavelength used is given in the right column. Data are band-pass filtered (200 – 3000 Hz). (B) Unfiltered extracellular voltage traces showing the induced activity in ON sustained retinal ganglion cells. A slow drift of the sensor signal is visible, which does not prevent detection of ganglion cell spiking. Figure 1 Acknowledgements This work was supported by a grant of the Federal Ministry for Education and Research /BMBF (FKZ 031L0059) Keywords: CMOS-MEA, ganglion cell, Optical stimulation, Mouse Retina Conference: MEA Meeting 2016 | 10th International Meeting on Substrate-Integrated Electrode Arrays, Reutlingen, Germany, 28 Jun - 1 Jul, 2016. Presentation Type: Poster Presentation Topic: MEA Meeting 2016 Citation: Jetter F, Bertotti G, Thewes R and Zeck G (2016). Wavelength-sensitivity of mouse retinal ganglion cells recorded by a high-density micro electrode array (MEA). Front. Neurosci. Conference Abstract: MEA Meeting 2016 | 10th International Meeting on Substrate-Integrated Electrode Arrays. doi: 10.3389/conf.fnins.2016.93.00097 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 22 Jun 2016; Published Online: 24 Jun 2016. * Correspondence: Dr. Günther Zeck, NMI at the University Tuebingen, Neurochip Research, Reutlingen, Germany, guenther.zeck@tuwien.ac.at Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Florian Jetter Gabriel Bertotti Roland Thewes Günther Zeck Google Florian Jetter Gabriel Bertotti Roland Thewes Günther Zeck Google Scholar Florian Jetter Gabriel Bertotti Roland Thewes Günther Zeck PubMed Florian Jetter Gabriel Bertotti Roland Thewes Günther Zeck Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

An overview and introduction is given concerning CMOS chips used for neural tissue interfacing. Some basics in the biological domain are discussed as well as extracellular neural tissue interfacing approaches, design philosophies applied to high spatiotemporal resolution devices, in-vitro and in-vivo applications, and related challenges in the engineering domain.

Event Abstract Back to Event In-Column Cross-Talk Suppression in High-Density CMOS-MEAs Gabriel Bertotti1, Günther Zeck2, Karl-Heinz Boven3 and Roland Thewes4* 1 Technische Universität Berlin, Chair of Sensor and Actuator Systems, Germany 2 NMI at the University Tuebingen, Neurochip Research, Germany 3 Multi Channel Systems MCS GmbH, Germany 4 Technische Universität Berlin, Chair of Sensor and Actuator Systems, Germany Motivation The high-density CMOS-MEA system introduced in [1], enabling simultaneous stimulation and recording [2], enables neural imaging at high spatial resolution thanks to its circuit topology in the readout path. However, this architecture also leads to a kind of “in-column cross-talk" if many sites belonging to the same column record highly-correlated signals which may occur under specific operating conditions. This is e.g. the case during electrical stimulation applied to a large portion of the entire active chip area or during system calibration by means of applying a calibration signal to the bath directly. In this work, we present a simple approach to model this type of cross-talk and use this model to post-process the recorded data in order to efficiently suppress cross-talk-related artifacts. Materials and Methods The high-density CMOS-based MEA used here [1, 3] has 4225 purely capacitively-coupled recording sites, which are organized in 65 rows and 65 columns as schematically shown in Fig. 1. Every sensing site consists of a sensor transistor, whose gate is capacitively coupled to the electrolyte through a metal electrode at the chip surface covered by a thin high-k dielectric. Local variations of the electrolyte potential induced by neural activity are converted into current signals by the sensor transistors. In order to achieve full imaging capability (readout from all available recording sites) multiplexing at column level is performed. Hence, only one column of sensor transistors is active within a given time frame. On this basis, the simplified small-signal equivalent circuit depicted in Fig. 2 can be derived. For the sake of simplicity, transistor parameter variations, channel length modulation-related effects, and parasitic resistances related to metal interconnects are neglected here. Resistor r_S models the resistance of the switch transistor, which connects the sensor transistor's source to bias voltage V_1. Resistor r_S leads to a so-called source degeneration which translates into in-column cross-talk. The following relation applies: --------> Here Formula #1 with --------> Here Formula #2 Moreover, g_S = 1/r_S and g_m stands for the sensor transistors' transconductance. This means that, for k=1...65, output current i_k depends on the signals recorded by all sensor transistors in the respective column (v_1 ... v_65 ), i.e. the considered output signal i_k is affected by cross-talk. It can be shown that matrix A_C is invertible, hence the original (cross-talk free) recorded signals can be recovered by multiplication of the recorded data by the inverse matrix A_C^-1. Since both g_m and g_s are operating point dependent and may vary from chip to chip, a calibration procedure is developed, which estimates the parameter y on the basis of a simple and straight-forward measurement. Results Two examples of successful in-column cross-talk artifact suppression are reported in Figs. 3 and 4, respectively. In both cases, in order to force the required signals to the different sensor transistors we take advantage of the programmable stimulation capability of the CMOS-MEA system (for details, see figure captions and [1, 3]). It is worth to note that both measurements are performed with the same MEA chip operated in the same operating point, so that only a one-time determination of matrix A_C^-1 is required for both signal post-processing procedures. Conclusion In this work, in-column cross-talk effects are investigated of the high-density CMOS-based MEA suggested in [1, 3]. A post-processing method for compensation of related cross-talk artifacts is proposed as well. Two exemplary experiments are reported, where successful compensation of cross-talk-related artifacts is achieved. References [1] Bertotti, G. et al., A CMOS-based sensor array for in-vitro neural tissue interfacing with 4225 recording sites and 1024 stimulation sites, IEEE Biomedical Circuits and Systems Conference (BioCAS), pp. 304-307, 2014. [2] Velychko, D. et al., Simultaneous stimulation and recording of retinal action potentials using capacitively coupled high-density CMOS-based MEAs, 9th International Meeting on Substrate- Integrated Microelectrode Arrays , pp. 78-79, 2014. [3] URL: http://www.multichannelsystems.com/ Figure Legend Fig. 1: Transistor-level representation and topology of the recording circuitry of the CMOS-MEA with high spatial resolution from [1, 3]. Fig. 2: Small-signal equivalent circuit of the array of sensor transistors. Note, that only the 65 transistors from an active column contribute to the output currents considered in the small-signal domain. Fig. 3: Example 1 of applied in-column cross-talk compensation. By means of electrical stimulation via the CMOS-MEA itself, all recording transistors inside the hatched region highlighted in the inset of the figure are forced to sense a sinusoidal signal. The recording site marked in red is outside the stimulation region and should therefore record only noise. Stimulation signal: 1Vpp @ 25Hz. Fig. 4: Example 2 of in-column cross-talk compensation. Stimulation signals: Area #1, 0.5Vpp @ 8.3Hz, Area #2, 1Vpp @ 25Hz. Figure 1 Acknowledgements Support and funding of this project by the German Ministry of Education and Research, Projektträger Jülich, and Projektträger VDI Technologiezentrum GmbH is gratefully acknowledged (references 0315636A and 1312038). Keywords: Electrical Stimulation, Signal analysis, CMOS-MEA, Cross-talk Conference: MEA Meeting 2016 | 10th International Meeting on Substrate-Integrated Electrode Arrays, Reutlingen, Germany, 28 Jun - 1 Jul, 2016. Presentation Type: Poster Presentation Topic: MEA Meeting 2016 Citation: Bertotti G, Zeck G, Boven K and Thewes R (2016). In-Column Cross-Talk Suppression in High-Density CMOS-MEAs. Front. Neurosci. Conference Abstract: MEA Meeting 2016 | 10th International Meeting on Substrate-Integrated Electrode Arrays. doi: 10.3389/conf.fnins.2016.93.00038 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 22 Jun 2016; Published Online: 24 Jun 2016. * Correspondence: Dr. Roland Thewes, Technische Universität Berlin, Chair of Sensor and Actuator Systems, Berlin, Germany, roland.thewes@tu-berlin.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Gabriel Bertotti Günther Zeck Karl-Heinz Boven Roland Thewes Google Gabriel Bertotti Günther Zeck Karl-Heinz Boven Roland Thewes Google Scholar Gabriel Bertotti Günther Zeck Karl-Heinz Boven Roland Thewes PubMed Gabriel Bertotti Günther Zeck Karl-Heinz Boven Roland Thewes Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

A CMOS MEA with 4k recording and 1k stimulation sites is used for time-continuous recording of neural signals during stimulation. All sites consist of thin metal electrodes on the chip surface covered by a thin high-k dielectric. Recording and stimulation channels are electrically separated but physically superimposed so that recording at the site of stimulation is possible as well as at any other location within the array. A compensation method is introduced to fully compensate for stimulation signal-induced artifacts in the recording channels. Measurement results reveal the feasibility of our approach.

Local field potentials (LFPs) contain relevant information about neuronal population activity [1]. They are commonly measured in the brain to investigate information processing by neural circuits and for neuroprosthetics applications. We present a novel method allowing for in vivo ‘electrical imaging’ of LFPs. An oxide-insulated neural probe was implanted in the brain of a rat, establishing a capacitive electrical coupling with the nervous tissue. Thanks to a multiplexed array of 256 capacitive micro electrodes, the probe could record two dimensional LFP profiles with unprecedented spatial resolution, down to fifteen micrometers. A recording example within a single-barrel of the somatosensory cortex of an anaesthetized rat is provided.

CMOS-based neural tissue in-vivo recording chips with a purely capacitive interface are presented with 256 sites resp. 256 recording channels. A 3D post-CMOS ALD-based process allows to provide a highly efficient sensor dielectric and to realize a protective insulation layer for the non-active part of the fabricated devices. A simple interconnect-efficient sensor array topology is used. Electrical characterizations and in-vivo measurements with biological content reveal proper operation of the presented approach.

A high spatiotemporal resolution, wireline operation-based, in-vivo neural recording system is presented. The proposed system allows selecting 64 channels from 512 recording sites. The neural signals from the 64 selected sites are amplified, filtered, and finally multiplexed in the time domain. The output signals of each multiplexer are buffered, converted to the current domain, and then transferred to off-chip units for further signal processing purposes. The proposed chip is simulated in a standard 180 nm CMOS process. Estimated input referred noise in the frequency band from 1 Hz to 10 kHz is 5.1 μV rms , and the total power consumption amounts to 3.3 mW at a supply voltage of 1.8 V.

Titanium dioxide, known as a high-k biocompatible dielectric transducer material, is processed by means of ALD and applied to a 3D structure with dimensions typical for multi-site multi-channel in-vivo neural interfaces. High uniformity, high areal capacitance, and in particular low leakage current densities are achieved within a sufficiently wide operation voltage window. The results demonstrate the suitability of this process to provide dielectric interfaces for 3D biomedical applications.

A CMOS-based microelectrode array (MEA) with 4225 recording sites and 1024 stimulation sites and a related data acquisition system are presented. The chip provides high spatiotemporal resolution on an active area of 1 mm × 1 mm or 2 mm × 2 mm, respectively, and allows in-vitro neural tissue interfacing experiments with full imaging capability. The entire chip surface is covered by a thin high-k dielectric layer so that electric coupling between biological tissue and solid-state chip is purely capacitive. Biological experiments reveal proper functionality of the system.

A CMOS-based MEA with 4225 recording sites and 1024 stimulation sites is used to achieve high spatiotemporal resolution in in-vitro neural tissue interfacing experiments. Active area is 1 mm × 1 mm or 2 mm × 2 mm, respectively. A thin high-k dielectric serves as sensor interface between solid-state chip and biology.

An 8 bit segmented current steering DAC is presented for the compensation of mismatch of sensors with current output arranged in a large arrays. The DAC is implemented in a 1.8 V supply voltage 180 nm standard CMOS technology. Post layout simulations reveal that the design target concerning a sampling frequency of 2.6 MHz is exceeded, worst-case settling time equals 60.6 ns. The output current range is 0–10 μA, which translates into an LSB of 40 nA. Good linearity is achieved, INL < 0.5 LSB and DNL < 0.4 LSB, respectively. Static power consumption with the outputs operated at a voltage of 0.9 V is approximately 10 μW. Dynamic power, mainly consumed by switching activity of the digital circuit parts, amounts to 100 μW at 2.6 MHz operation frequency. Total area is 38.6 × 2933.0 μm2.