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2022
	Xue, Xiaohan ; Buccino, Alessio Paolo ; Kumar, Sreedhar Saseendran ; Hierlemann, Andreas ; Bartram, Julian Inferring monosynaptic connections from paired dendritic spine Ca2+ imaging and large-scale recording of extracellular spiking Journal Article bioRxiv, 2022. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks @article{Xue2022, title = {Inferring monosynaptic connections from paired dendritic spine Ca2+ imaging and large-scale recording of extracellular spiking}, author = {Xue, Xiaohan and Buccino, Alessio Paolo and Kumar, Sreedhar Saseendran and Hierlemann, Andreas and Bartram, Julian}, doi = {10.1101/2022.02.16.480643}, year = {2022}, date = {2022-02-16}, journal = {bioRxiv}, abstract = {Techniques to identify monosynaptic connections between neurons have been vital for neuroscience research, facilitating important advancements concerning network topology, synaptic plasticity, and synaptic integration, among others. Here, we introduce a novel approach to identify and monitor monosynaptic connections using high-resolution dendritic spine Ca2+ imaging combined with simultaneous large-scale recording of extracellular electrical activity by means of high-density microelectrode arrays (HD-MEAs). We introduce an easily adoptable analysis pipeline that associates the imaged spine with its presynaptic unit and test it on in vitro recordings. The method is further validated and optimized by simulating synaptically-evoked spine Ca2+ transients based on measured spike trains in order to obtain simulated ground-truth connections. The proposed approach offers unique advantages as i) it can be used to identify monosynaptic connections with an accurate localization of the synapse within the dendritic tree, ii) it provides precise information of presynaptic spiking, and iii) postsynaptic spine Ca2+ signals and, finally, iv) the non-invasive nature of the proposed method allows for long-term measurements. The analysis toolkit together with the rich data sets that were acquired are made publicly available for further exploration by the research community.}, keywords = {ETH-CMOS-MEA, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close Techniques to identify monosynaptic connections between neurons have been vital for neuroscience research, facilitating important advancements concerning network topology, synaptic plasticity, and synaptic integration, among others. Here, we introduce a novel approach to identify and monitor monosynaptic connections using high-resolution dendritic spine Ca2+ imaging combined with simultaneous large-scale recording of extracellular electrical activity by means of high-density microelectrode arrays (HD-MEAs). We introduce an easily adoptable analysis pipeline that associates the imaged spine with its presynaptic unit and test it on in vitro recordings. The method is further validated and optimized by simulating synaptically-evoked spine Ca2+ transients based on measured spike trains in order to obtain simulated ground-truth connections. The proposed approach offers unique advantages as i) it can be used to identify monosynaptic connections with an accurate localization of the synapse within the dendritic tree, ii) it provides precise information of presynaptic spiking, and iii) postsynaptic spine Ca2+ signals and, finally, iv) the non-invasive nature of the proposed method allows for long-term measurements. The analysis toolkit together with the rich data sets that were acquired are made publicly available for further exploration by the research community. Close doi:10.1101/2022.02.16.480643 Close
2021
	Kagan, Brett J; Kitchen, Andy C; Tran, Nhi T; Parker, Bradyn J; Bhat, Anjali; Rollo, Ben; Razi, Adeel; Friston, Karl J In vitro neurons learn and exhibit sentience when embodied in a simulated game-world Journal Article BioRxiv, 2021. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, In-Vitro, MaxOne @article{Kagan2021, title = {In vitro neurons learn and exhibit sentience when embodied in a simulated game-world}, author = {Brett J. Kagan and Andy C. Kitchen and Nhi T. Tran and Bradyn J. Parker and Anjali Bhat and Ben Rollo and Adeel Razi and Karl J. Friston}, url = {https://www.biorxiv.org/content/10.1101/2021.12.02.471005v1 }, doi = {10.1101/2021.12.02.471005}, year = {2021}, date = {2021-12-03}, journal = {BioRxiv}, abstract = {Human brain organoids replicate much of the cellular diversity and developmental anatomy of the human brain. However, the physiological behavior of neuronal circuits within organoids remains relatively under-explored. With high-density CMOS microelectrode arrays (26,400 electrodes) and shank electrodes (960 electrodes), we probed broadband and three-dimensional extracellular field recordings generated by spontaneous activity of human brain organoids. These recordings simultaneously captured local field potentials (LFPs) and single-unit activity extracted through spike sorting. From spiking activity, we estimated a directed functional connectivity graph of synchronous neural network activity, which showed a large number of weak functional connections enmeshed within a network skeleton of significantly fewer strong connections. Treatment of the organoid with a benzodiazepine induced a reproducible signature response that shortened the inter-burst intervals, increased the uniformity of the firing pattern within each burst and decreased the population of weakly connected edges. Simultaneously examining the spontaneous LFPs and their phase alignment to spiking showed that spike bursts were coherent with theta oscillations in the LFPs. Our results demonstrate that human brain organoids have self-organized neuronal assemblies of sufficient size, cellular orientation, and functional connectivity to co-activate and generate field potentials from their collective transmembrane currents that phase-lock to spiking activity. These results point to the potential of brain organoids for the study of neuropsychiatric diseases, drug mechanisms, and the effects of external stimuli upon neuronal networks.}, keywords = {ETH-CMOS-MEA, In-Vitro, MaxOne}, pubstate = {published}, tppubtype = {article} } Close Human brain organoids replicate much of the cellular diversity and developmental anatomy of the human brain. However, the physiological behavior of neuronal circuits within organoids remains relatively under-explored. With high-density CMOS microelectrode arrays (26,400 electrodes) and shank electrodes (960 electrodes), we probed broadband and three-dimensional extracellular field recordings generated by spontaneous activity of human brain organoids. These recordings simultaneously captured local field potentials (LFPs) and single-unit activity extracted through spike sorting. From spiking activity, we estimated a directed functional connectivity graph of synchronous neural network activity, which showed a large number of weak functional connections enmeshed within a network skeleton of significantly fewer strong connections. Treatment of the organoid with a benzodiazepine induced a reproducible signature response that shortened the inter-burst intervals, increased the uniformity of the firing pattern within each burst and decreased the population of weakly connected edges. Simultaneously examining the spontaneous LFPs and their phase alignment to spiking showed that spike bursts were coherent with theta oscillations in the LFPs. Our results demonstrate that human brain organoids have self-organized neuronal assemblies of sufficient size, cellular orientation, and functional connectivity to co-activate and generate field potentials from their collective transmembrane currents that phase-lock to spiking activity. These results point to the potential of brain organoids for the study of neuropsychiatric diseases, drug mechanisms, and the effects of external stimuli upon neuronal networks. Close https://www.biorxiv.org/content/10.1101/2021.12.02.471005v1 doi:10.1101/2021.12.02.471005 Close
	Sundberg, Maria; Pinson, Hannah; Smith, Richard S; Winden, Kellen D; Venugopal, Pooja; Tai, Derek J C; Gusella, James F; Talkowski, Michael E; Walsh, Christopher A; Tegmark, Max; Sahin, Mustafa 16p11.2 deletion is associated with hyperactivation of human iPSC-derived dopaminergic neuron networks and is rescued by RHOA inhibition in vitro Journal Article Nature Communications, 12 (2897 ), 2021. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, IPSC, MaxOne @article{Sundberg2021, title = {16p11.2 deletion is associated with hyperactivation of human iPSC-derived dopaminergic neuron networks and is rescued by RHOA inhibition in vitro}, author = {Maria Sundberg and Hannah Pinson and Richard S. Smith and Kellen D. Winden and Pooja Venugopal and Derek J. C. Tai and James F. Gusella and Michael E. Talkowski and Christopher A. Walsh and Max Tegmark and Mustafa Sahin }, url = {https://www.nature.com/articles/s41467-021-23113-z}, doi = {10.1038/s41467-021-23113-z}, year = {2021}, date = {2021-05-18}, journal = {Nature Communications}, volume = {12}, number = {2897 }, abstract = {Reciprocal copy number variations (CNVs) of 16p11.2 are associated with a wide spectrum of neuropsychiatric and neurodevelopmental disorders. Here, we use human induced pluripotent stem cells (iPSCs)-derived dopaminergic (DA) neurons carrying CNVs of 16p11.2 duplication (16pdup) and 16p11.2 deletion (16pdel), engineered using CRISPR-Cas9. We show that 16pdel iPSC-derived DA neurons have increased soma size and synaptic marker expression compared to isogenic control lines, while 16pdup iPSC-derived DA neurons show deficits in neuronal differentiation and reduced synaptic marker expression. The 16pdel iPSC-derived DA neurons have impaired neurophysiological properties. The 16pdel iPSC-derived DA neuronal networks are hyperactive and have increased bursting in culture compared to controls. We also show that the expression of RHOA is increased in the 16pdel iPSC-derived DA neurons and that treatment with a specific RHOA-inhibitor, Rhosin, rescues the network activity of the 16pdel iPSC-derived DA neurons. Our data suggest that 16p11.2 deletion-associated iPSC-derived DA neuron hyperactivation can be rescued by RHOA inhibition.}, keywords = {ETH-CMOS-MEA, IPSC, MaxOne}, pubstate = {published}, tppubtype = {article} } Close Reciprocal copy number variations (CNVs) of 16p11.2 are associated with a wide spectrum of neuropsychiatric and neurodevelopmental disorders. Here, we use human induced pluripotent stem cells (iPSCs)-derived dopaminergic (DA) neurons carrying CNVs of 16p11.2 duplication (16pdup) and 16p11.2 deletion (16pdel), engineered using CRISPR-Cas9. We show that 16pdel iPSC-derived DA neurons have increased soma size and synaptic marker expression compared to isogenic control lines, while 16pdup iPSC-derived DA neurons show deficits in neuronal differentiation and reduced synaptic marker expression. The 16pdel iPSC-derived DA neurons have impaired neurophysiological properties. The 16pdel iPSC-derived DA neuronal networks are hyperactive and have increased bursting in culture compared to controls. We also show that the expression of RHOA is increased in the 16pdel iPSC-derived DA neurons and that treatment with a specific RHOA-inhibitor, Rhosin, rescues the network activity of the 16pdel iPSC-derived DA neurons. Our data suggest that 16p11.2 deletion-associated iPSC-derived DA neuron hyperactivation can be rescued by RHOA inhibition. Close https://www.nature.com/articles/s41467-021-23113-z doi:10.1038/s41467-021-23113-z Close
	Yuan, Xinyue; Hierlemann, Andreas; Frey, Urs Extracellular Recording of Entire Neural Networks Using a Dual-Mode Microelectrode Array With 19,584 Electrodes and High SNR Journal Article IEEE, 2021. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MEA Technology @article{Yuan2021, title = {Extracellular Recording of Entire Neural Networks Using a Dual-Mode Microelectrode Array With 19,584 Electrodes and High SNR}, author = {Xinyue Yuan and Andreas Hierlemann and Urs Frey}, url = {https://ieeexplore.ieee.org/document/9385387}, doi = {10.1109/JSSC.2021.3066043}, year = {2021}, date = {2021-03-24}, journal = {IEEE}, abstract = {Electrophysiological research on neural networks and their activity focuses on the recording and analysis of large data sets that include information of thousands of neurons. CMOS microelectrode arrays (MEAs) feature thousands of electrodes at a spatial resolution on the scale of single cells and are, therefore, ideal tools to support neural-network research. Moreover, they offer high spatio-temporal resolution and signal-to-noise ratio (SNR) to capture all features and subcellular-resolution details of neuronal signaling. Here, we present a dual-mode (DM) MEA, which enables simultaneous: 1) full-frame readout from all electrodes and 2) high-SNR readout from an arbitrarily selectable subset of electrodes. The DM-MEA includes 19,584 electrodes, 19,584 full-frame recording channels with noise levels of 10.4 μVrms in the action potential (AP) frequency band (300 Hz-5 kHz), 246 low-noise recording channels with noise levels of 3.0 μVrms in the AP band and eight stimulation units. The capacity to simultaneously perform full-frame and high-SNR recordings endows the presented DM-MEA with great flexibility for various applications in neuroscience and pharmacology.}, keywords = {ETH-CMOS-MEA, MEA Technology}, pubstate = {published}, tppubtype = {article} } Close Electrophysiological research on neural networks and their activity focuses on the recording and analysis of large data sets that include information of thousands of neurons. CMOS microelectrode arrays (MEAs) feature thousands of electrodes at a spatial resolution on the scale of single cells and are, therefore, ideal tools to support neural-network research. Moreover, they offer high spatio-temporal resolution and signal-to-noise ratio (SNR) to capture all features and subcellular-resolution details of neuronal signaling. Here, we present a dual-mode (DM) MEA, which enables simultaneous: 1) full-frame readout from all electrodes and 2) high-SNR readout from an arbitrarily selectable subset of electrodes. The DM-MEA includes 19,584 electrodes, 19,584 full-frame recording channels with noise levels of 10.4 μVrms in the action potential (AP) frequency band (300 Hz-5 kHz), 246 low-noise recording channels with noise levels of 3.0 μVrms in the AP band and eight stimulation units. The capacity to simultaneously perform full-frame and high-SNR recordings endows the presented DM-MEA with great flexibility for various applications in neuroscience and pharmacology. Close https://ieeexplore.ieee.org/document/9385387 doi:10.1109/JSSC.2021.3066043 Close
	Ronchi, Silvia; Buccino, Alessio Paolo; Prack, Gustavo; Kumar, Sreedhar Saseendran; Schröter, Manuel; Fiscella, Michele; Hierlemann, Andreas Microelectrode Arrays: Electrophysiological Phenotype Characterization of Human iPSC-Derived Neuronal Cell Lines by Means of High-Density Microelectrode Arrays Journal Article Advanced Biology, 5 (3), 2021. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, IPSC @article{Ronchi2021, title = {Microelectrode Arrays: Electrophysiological Phenotype Characterization of Human iPSC-Derived Neuronal Cell Lines by Means of High-Density Microelectrode Arrays}, author = {Silvia Ronchi and Alessio Paolo Buccino and Gustavo Prack and Sreedhar Saseendran Kumar and Manuel Schröter and Michele Fiscella and Andreas Hierlemann}, url = {https://onlinelibrary.wiley.com/doi/10.1002/adbi.202000223}, doi = {10.1002/adbi.202000223}, year = {2021}, date = {2021-03-17}, journal = {Advanced Biology}, volume = {5}, number = {3}, abstract = {In article number 2000223, Silvia Ronchi, Michele Fiscella, and co-workers show neurons plated on a high-density microelectrode array. The small electrode size and the tight spacing between the 26 400 electrodes enable functional extracellular electrophysiological characterization of neurons across scales, from subcellular-resolution features, like axons and dendrites, through individual neuronal cells to entire networks.}, keywords = {ETH-CMOS-MEA, IPSC}, pubstate = {published}, tppubtype = {article} } Close In article number 2000223, Silvia Ronchi, Michele Fiscella, and co-workers show neurons plated on a high-density microelectrode array. The small electrode size and the tight spacing between the 26 400 electrodes enable functional extracellular electrophysiological characterization of neurons across scales, from subcellular-resolution features, like axons and dendrites, through individual neuronal cells to entire networks. Close https://onlinelibrary.wiley.com/doi/10.1002/adbi.202000223 doi:10.1002/adbi.202000223 Close
	Sharf, Tal; van der Molen, Tjitse; Guzman, Elmer; Glasauer, Stella M K; Luna, Gabriel; Cheng, Zhouwei; Audouard, Morgane; Ranasinghe, Kamalini G; Kudo, Kiwamu; Nagarajan, Srikantan S; Tovar, Kenneth R; Petzold, Linda R; Hansma, Paul K; Kosik, Kenneth S Intrinsic network activity in human brain organoids Journal Article BioRxiv, 2021. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks, Organoids @article{Sharf2021, title = {Intrinsic network activity in human brain organoids}, author = {Tal Sharf and Tjitse van der Molen and Elmer Guzman and Stella M.K. Glasauer and Gabriel Luna and Zhouwei Cheng and Morgane Audouard and Kamalini G. Ranasinghe and Kiwamu Kudo and Srikantan S. Nagarajan and Kenneth R. Tovar and Linda R. Petzold and Paul K. Hansma and Kenneth S. Kosik}, url = {https://www.biorxiv.org/content/10.1101/2021.01.28.428643v1}, doi = {10.1101/2021.01.28.428643}, year = {2021}, date = {2021-01-28}, journal = {BioRxiv}, abstract = {Human brain organoids replicate much of the cellular diversity and developmental anatomy of the human brain. However, the physiological behavior of neuronal circuits within organoids remains relatively under-explored. With high-density CMOS microelectrode arrays and shank electrodes, we probed broadband and three-dimensional spontaneous activity of human brain organoids. These recordings simultaneously captured local field potentials (LFPs) and single unit activity. From spiking activity, we estimated a directed functional connectivity graph of synchronous neural network activity which showed a large number of weak functional connections enmeshed within a network skeleton of significantly fewer strong connections. Increasing the intrinsic inhibitory tone with a benzodiazepine altered the functional network graph of the organoid by suppressing the network skeleton. Simultaneously examining the spontaneous LFPs and their phase alignment to spiking showed that spike bursts were coherent with theta oscillations in the LFPs. An ensemble of spikes phase-locked to theta frequency oscillations were strongly interconnected as a sub-network within the larger network in which they were embedded. Our results demonstrate that human brain organoids have self-organized neuronal assemblies of sufficient size, cellular orientation, and functional connectivity to co-activate and generate field potentials from their collective transmembrane currents that phase-lock to spiking activity. These results point to the potential of brain organoids for the study of neuropsychiatric diseases, drug mechanisms, and the effects of external stimuli upon neuronal networks.}, keywords = {ETH-CMOS-MEA, Neuronal Networks, Organoids}, pubstate = {published}, tppubtype = {article} } Close Human brain organoids replicate much of the cellular diversity and developmental anatomy of the human brain. However, the physiological behavior of neuronal circuits within organoids remains relatively under-explored. With high-density CMOS microelectrode arrays and shank electrodes, we probed broadband and three-dimensional spontaneous activity of human brain organoids. These recordings simultaneously captured local field potentials (LFPs) and single unit activity. From spiking activity, we estimated a directed functional connectivity graph of synchronous neural network activity which showed a large number of weak functional connections enmeshed within a network skeleton of significantly fewer strong connections. Increasing the intrinsic inhibitory tone with a benzodiazepine altered the functional network graph of the organoid by suppressing the network skeleton. Simultaneously examining the spontaneous LFPs and their phase alignment to spiking showed that spike bursts were coherent with theta oscillations in the LFPs. An ensemble of spikes phase-locked to theta frequency oscillations were strongly interconnected as a sub-network within the larger network in which they were embedded. Our results demonstrate that human brain organoids have self-organized neuronal assemblies of sufficient size, cellular orientation, and functional connectivity to co-activate and generate field potentials from their collective transmembrane currents that phase-lock to spiking activity. These results point to the potential of brain organoids for the study of neuropsychiatric diseases, drug mechanisms, and the effects of external stimuli upon neuronal networks. Close https://www.biorxiv.org/content/10.1101/2021.01.28.428643v1 doi:10.1101/2021.01.28.428643 Close
2020
	Yuan, Xinyue; Schröter, Manuel; Obien, Marie Engelene J; Fiscella, Michele; Gong, Wei; Kikuchi, Tetsuhiro; Odawara, Aoi; Noji, Shuhei; Suzuki, Ikuro; Takahashi, Jun; Hierlemann, Andreas; Frey, Urs Versatile live-cell activity analysis platform for characterization of neuronal dynamics at single-cell and network level Journal Article Nature Communications, 11 (4854), 2020. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MEA Technology @article{Yuan2020, title = {Versatile live-cell activity analysis platform for characterization of neuronal dynamics at single-cell and network level}, author = {Xinyue Yuan and Manuel Schröter and Marie Engelene J. Obien and Michele Fiscella and Wei Gong and Tetsuhiro Kikuchi and Aoi Odawara and Shuhei Noji and Ikuro Suzuki and Jun Takahashi and Andreas Hierlemann and Urs Frey}, url = {https://www.nature.com/articles/s41467-020-18620-4#citeas}, doi = {10.1038/s41467-020-18620-4}, year = {2020}, date = {2020-09-25}, journal = {Nature Communications}, volume = {11}, number = {4854}, abstract = {Chronic imaging of neuronal networks in vitro has provided fundamental insights into mechanisms underlying neuronal function. Current labeling and optical imaging methods, however, cannot be used for continuous and long-term recordings of the dynamics and evolution of neuronal networks, as fluorescent indicators can cause phototoxicity. Here, we introduce a versatile platform for label-free, comprehensive and detailed electrophysiological live-cell imaging of various neurogenic cells and tissues over extended time scales. We report on a dual-mode high-density microelectrode array, which can simultaneously record in (i) full-frame mode with 19,584 recording sites and (ii) high-signal-to-noise mode with 246 channels. We set out to demonstrate the capabilities of this platform with recordings from primary and iPSC-derived neuronal cultures and tissue preparations over several weeks, providing detailed morpho-electrical phenotypic parameters at subcellular, cellular and network level. Moreover, we develop reliable analysis tools, which drastically increase the throughput to infer axonal morphology and conduction speed.}, keywords = {ETH-CMOS-MEA, MEA Technology}, pubstate = {published}, tppubtype = {article} } Close Chronic imaging of neuronal networks in vitro has provided fundamental insights into mechanisms underlying neuronal function. Current labeling and optical imaging methods, however, cannot be used for continuous and long-term recordings of the dynamics and evolution of neuronal networks, as fluorescent indicators can cause phototoxicity. Here, we introduce a versatile platform for label-free, comprehensive and detailed electrophysiological live-cell imaging of various neurogenic cells and tissues over extended time scales. We report on a dual-mode high-density microelectrode array, which can simultaneously record in (i) full-frame mode with 19,584 recording sites and (ii) high-signal-to-noise mode with 246 channels. We set out to demonstrate the capabilities of this platform with recordings from primary and iPSC-derived neuronal cultures and tissue preparations over several weeks, providing detailed morpho-electrical phenotypic parameters at subcellular, cellular and network level. Moreover, we develop reliable analysis tools, which drastically increase the throughput to infer axonal morphology and conduction speed. Close https://www.nature.com/articles/s41467-020-18620-4#citeas doi:10.1038/s41467-020-18620-4 Close
	Cowan, Cameron S; Renner, Magdalena; Gennaro, Martina De; Gross-Scherf, Brigitte; Goldblum, David; Hou, Yanyan; Munz, Martin; Rodrigues, Tiago M; Krol, Jacek; Szikra, Tamas; Cuttat, Rachel; Waldt, Annick; Papasaikas, Panagiotis; Diggelmann, Roland; Patino-Alvarez, Claudia P; Galliker, Patricia; Spirig, Stefan E; Pavlinic, Dinko; Gerber-Hollbach, Nadine; Schuierer, Sven; Srdanovic, Aldin; Balogh, Marton; Panero, Riccardo; Kusnyerik, Akos; Szabo, Arnold; Stadler, Michael B; Orgül, Selim; Picelli, Simone; Hasler, Pascal W; Hierlemann, Andreas; Scholl, Hendrik P N; Roma, Guglielmo; Nigsch, Florian; Roska, Botond Cell Types of the Human Retina and Its Organoids at Single-Cell Resolution Journal Article CellPress, 182 , pp. 1623–1640, 2020. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Organoids @article{Cowan2020, title = {Cell Types of the Human Retina and Its Organoids at Single-Cell Resolution}, author = {Cameron S. Cowan and Magdalena Renner and Martina De Gennaro and Brigitte Gross-Scherf and David Goldblum and Yanyan Hou and Martin Munz and Tiago M. Rodrigues and Jacek Krol and Tamas Szikra and Rachel Cuttat and Annick Waldt and Panagiotis Papasaikas and Roland Diggelmann and Claudia P. Patino-Alvarez and Patricia Galliker and Stefan E. Spirig and Dinko Pavlinic and Nadine Gerber-Hollbach and Sven Schuierer and Aldin Srdanovic and Marton Balogh and Riccardo Panero and Akos Kusnyerik and Arnold Szabo and Michael B. Stadler and Selim Orgül and Simone Picelli and Pascal W. Hasler and Andreas Hierlemann and Hendrik P.N. Scholl and Guglielmo Roma and Florian Nigsch and Botond Roska}, url = {https://www.cell.com/cell/fulltext/S0092-8674(20)31004-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420310047%3Fshowall%3Dtrue}, doi = {10.1016/j.cell.2020.08.013}, year = {2020}, date = {2020-09-17}, journal = {CellPress}, volume = {182}, pages = { 1623–1640}, abstract = {Human organoids recapitulating the cell-type diversity and function of their target organ are valuable for basic and translational research. We developed light-sensitive human retinal organoids with multiple nuclear and synaptic layers and functional synapses. We sequenced the RNA of 285,441 single cells from these organoids at seven developmental time points and from the periphery, fovea, pigment epithelium and choroid of light-responsive adult human retinas, and performed histochemistry. Cell types in organoids matured in vitro to a stable “developed” state at a rate similar to human retina development in vivo. Transcriptomes of organoid cell types converged toward the transcriptomes of adult peripheral retinal cell types. Expression of disease-associated genes was cell-type-specific in adult retina, and cell-type specificity was retained in organoids. We implicate unexpected cell types in diseases such as macular degeneration. This resource identifies cellular targets for studying disease mechanisms in organoids and for targeted repair in human retinas.}, keywords = {ETH-CMOS-MEA, Organoids}, pubstate = {published}, tppubtype = {article} } Close Human organoids recapitulating the cell-type diversity and function of their target organ are valuable for basic and translational research. We developed light-sensitive human retinal organoids with multiple nuclear and synaptic layers and functional synapses. We sequenced the RNA of 285,441 single cells from these organoids at seven developmental time points and from the periphery, fovea, pigment epithelium and choroid of light-responsive adult human retinas, and performed histochemistry. Cell types in organoids matured in vitro to a stable “developed” state at a rate similar to human retina development in vivo. Transcriptomes of organoid cell types converged toward the transcriptomes of adult peripheral retinal cell types. Expression of disease-associated genes was cell-type-specific in adult retina, and cell-type specificity was retained in organoids. We implicate unexpected cell types in diseases such as macular degeneration. This resource identifies cellular targets for studying disease mechanisms in organoids and for targeted repair in human retinas. Close https://www.cell.com/cell/fulltext/S0092-8674(20)31004-7?_returnURL=https%3A%2F%[...] doi:10.1016/j.cell.2020.08.013 Close
	Ronchi, Silvia; Buccino, Alessio Paolo; Prack, Gustavo; Kumar, Sreedhar Saseendran; Schröter, Manuel; Fiscella, Michele; Hierlemann, Andreas Electrophysiological Phenotype Characterization of Human iPSC-Derived Neuronal Cell Lines by Means of High-Density Microelectrode Arrays Journal Article BioRxiv, 2020. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, IPSC @article{Ronchi2020, title = {Electrophysiological Phenotype Characterization of Human iPSC-Derived Neuronal Cell Lines by Means of High-Density Microelectrode Arrays}, author = {Silvia Ronchi and Alessio Paolo Buccino and Gustavo Prack and Sreedhar Saseendran Kumar and Manuel Schröter and Michele Fiscella and Andreas Hierlemann }, url = {https://www.biorxiv.org/content/10.1101/2020.09.02.271403v1}, doi = {10.1101/2020.09.02.271403}, year = {2020}, date = {2020-09-02}, journal = {BioRxiv}, abstract = {Recent advances in the field of cellular reprogramming have opened a route to study the fundamental mechanisms underlying common neurological disorders. High-density microelectrode-arrays (HD-MEAs) provide unprecedented means to study neuronal physiology at different scales, ranging from network through single-neuron to subcellular features. In this work, we used HD-MEAs in vitro to characterize and compare human induced-pluripotent-stem-cell (iPSC)-derived dopaminergic and motor neurons, including isogenic neuronal lines modeling Parkinson’s disease and amyotrophic lateral sclerosis. We established reproducible electrophysiological network, single-cell and subcellular metrics, which were used for phenotype characterization and drug testing. Metrics such as burst shapes and axonal velocity enabled the distinction of healthy and diseased neurons. The HD-MEA metrics could also be used to detect the effects of dosing the drug retigabine to human motor neurons. Finally, we showed that the ability to detect drug effects and the observed culture-to-culture variability critically depend on the number of available recording electrodes}, keywords = {ETH-CMOS-MEA, IPSC}, pubstate = {published}, tppubtype = {article} } Close Recent advances in the field of cellular reprogramming have opened a route to study the fundamental mechanisms underlying common neurological disorders. High-density microelectrode-arrays (HD-MEAs) provide unprecedented means to study neuronal physiology at different scales, ranging from network through single-neuron to subcellular features. In this work, we used HD-MEAs in vitro to characterize and compare human induced-pluripotent-stem-cell (iPSC)-derived dopaminergic and motor neurons, including isogenic neuronal lines modeling Parkinson’s disease and amyotrophic lateral sclerosis. We established reproducible electrophysiological network, single-cell and subcellular metrics, which were used for phenotype characterization and drug testing. Metrics such as burst shapes and axonal velocity enabled the distinction of healthy and diseased neurons. The HD-MEA metrics could also be used to detect the effects of dosing the drug retigabine to human motor neurons. Finally, we showed that the ability to detect drug effects and the observed culture-to-culture variability critically depend on the number of available recording electrodes Close https://www.biorxiv.org/content/10.1101/2020.09.02.271403v1 doi:10.1101/2020.09.02.271403 Close
	Idrees, Saad; Baumann, Matthias P; Franke, Felix; Münch, Thomas A; Hafed, Ziad M Perceptual saccadic suppression starts in the retina Journal Article Nature Communications, 11 (1977), 2020. Links \| BibTeX \| Tags: ETH-CMOS-MEA, MaxOne, Retina @article{Idrees2020, title = {Perceptual saccadic suppression starts in the retina}, author = {Saad Idrees and Matthias P. Baumann and Felix Franke and Thomas A. Münch and Ziad M. Hafed}, url = {https://www.nature.com/articles/s41467-020-15890-w}, doi = {10.1038/s41467-020-15890-w}, year = {2020}, date = {2020-04-24}, journal = {Nature Communications}, volume = {11}, number = {1977}, keywords = {ETH-CMOS-MEA, MaxOne, Retina}, pubstate = {published}, tppubtype = {article} } Close https://www.nature.com/articles/s41467-020-15890-w doi:10.1038/s41467-020-15890-w Close
	Obaid, Abdulmalik; Hanna, Mina-Elrahb; Wu, Yu-Wei; Kollo, Mihaly; Racz, Romeo; Angle, Matthew R; Muller, Jan; Brackbill, Nora; Wray, William; Franke, Felix; Chichilnski, E J; Hierlemann, Andreas; Ding, Jun B; Schaefer, Andreas T; Melosh, Nicholas A Massively parallel microwire arrays integrated withCMOS chips for neural recording Journal Article Science Advances, 2020. Abstract \| Links \| BibTeX \| Tags: Electrodes, ETH-CMOS-MEA @article{Obaid2020, title = {Massively parallel microwire arrays integrated withCMOS chips for neural recording}, author = {Abdulmalik Obaid and Mina-Elrahb Hanna and Yu-Wei Wu and Mihaly Kollo and Romeo Racz and Matthew R Angle and Jan Muller and Nora Brackbill and William Wray and Felix Franke and E J Chichilnski and Andreas Hierlemann and Jun B. Ding and Andreas T. Schaefer and Nicholas A. Melosh}, url = {https://advances.sciencemag.org/content/6/12/eaay2789}, doi = {10.1126/sciadv.aay2789}, year = {2020}, date = {2020-03-20}, journal = {Science Advances}, abstract = {Multi-channel electrical recordings of neural activity in the brain is an increasingly powerful method revealing new aspects of neural communication, computation, and prosthetics. However, while planar silicon-based CMOS devices in conventional electronics scale rapidly, neural interface devices have not kept pace. Here, we present a new strategy to interface silicon-based chips with three-dimensional microwire arrays, providing the link between rapidly-developing electronics and high density neural interfaces. The system consists of a bundle of microwires mated to large-scale microelectrode arrays, such as camera chips. This system has excellent recording performance, demonstrated via single unit and local-field potential recordings in isolated retina and in the motor cortex or striatum of awake moving mice. The modular design enables a variety of microwire types and sizes to be integrated with different types of pixel arrays, connecting the rapid progress of commercial multiplexing, digitisation and data acquisition hardware together with a three-dimensional neural interface.}, keywords = {Electrodes, ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close Multi-channel electrical recordings of neural activity in the brain is an increasingly powerful method revealing new aspects of neural communication, computation, and prosthetics. However, while planar silicon-based CMOS devices in conventional electronics scale rapidly, neural interface devices have not kept pace. Here, we present a new strategy to interface silicon-based chips with three-dimensional microwire arrays, providing the link between rapidly-developing electronics and high density neural interfaces. The system consists of a bundle of microwires mated to large-scale microelectrode arrays, such as camera chips. This system has excellent recording performance, demonstrated via single unit and local-field potential recordings in isolated retina and in the motor cortex or striatum of awake moving mice. The modular design enables a variety of microwire types and sizes to be integrated with different types of pixel arrays, connecting the rapid progress of commercial multiplexing, digitisation and data acquisition hardware together with a three-dimensional neural interface. Close https://advances.sciencemag.org/content/6/12/eaay2789 doi:10.1126/sciadv.aay2789 Close
2019
	Ronchi, Silvia; Fiscella, Michele; Marchetti, Camilla; Viswam, Vijay; Muller, Jan; Frey, Urs; Hierlemann, Andreas Single-Cell Electrical Stimulation Using CMOS-Based High-Density Microelectrode Arrays Journal Article Frontiers in Neuroscience, 13 , 2019, ISSN: 1662-453X . Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Stimulation @article{Ronchi2019, title = {Single-Cell Electrical Stimulation Using CMOS-Based High-Density Microelectrode Arrays}, author = {Silvia Ronchi and Michele Fiscella and Camilla Marchetti and Vijay Viswam and Jan Muller and Urs Frey and Andreas Hierlemann}, url = {https://www.frontiersin.org/article/10.3389/fnins.2019.00208 }, doi = {10.3389/fnins.2019.00208 }, issn = {1662-453X }, year = {2019}, date = {2019-03-13}, journal = {Frontiers in Neuroscience}, volume = {13}, abstract = {Non-invasive electrical stimulation can be used to study and control neural activity in the brain or to alleviate somatosensory dysfunctions. One intriguing prospect is to precisely stimulate individual targeted neurons. Here, we investigated single-neuron current and voltage stimulation in vitro using high-density microelectrode arrays featuring 26’400 bidirectional electrodes at a pitch of 17.5 µm and an electrode area of 5 × 9 µm². We determined optimal waveforms, amplitudes and durations for both stimulation modes. Owing to the high spatial resolution of our arrays and the close proximity of the electrodes to the respective neurons, we were able to stimulate the axon initial segments (AIS) with charges of less than 2 picoCoulombs. This resulted in minimal artifact production and reliable readout of stimulation efficiency directly at the soma of the stimulated cell. Stimulation signals as low as 70 mV or 100 nA,with pulse durations as short as 18 µs, yielded measurable action potential initiation and propagation. We found that the required stimulation signal amplitudes decreased with cell growth and development and that stimulation efficiency did not improve at higher electric fields generated by simultaneous multi-electrode stimulation.}, keywords = {ETH-CMOS-MEA, Stimulation}, pubstate = {published}, tppubtype = {article} } Close Non-invasive electrical stimulation can be used to study and control neural activity in the brain or to alleviate somatosensory dysfunctions. One intriguing prospect is to precisely stimulate individual targeted neurons. Here, we investigated single-neuron current and voltage stimulation in vitro using high-density microelectrode arrays featuring 26’400 bidirectional electrodes at a pitch of 17.5 µm and an electrode area of 5 × 9 µm². We determined optimal waveforms, amplitudes and durations for both stimulation modes. Owing to the high spatial resolution of our arrays and the close proximity of the electrodes to the respective neurons, we were able to stimulate the axon initial segments (AIS) with charges of less than 2 picoCoulombs. This resulted in minimal artifact production and reliable readout of stimulation efficiency directly at the soma of the stimulated cell. Stimulation signals as low as 70 mV or 100 nA,with pulse durations as short as 18 µs, yielded measurable action potential initiation and propagation. We found that the required stimulation signal amplitudes decreased with cell growth and development and that stimulation efficiency did not improve at higher electric fields generated by simultaneous multi-electrode stimulation. Close https://www.frontiersin.org/article/10.3389/fnins.2019.00208 doi:10.3389/fnins.2019.00208 Close
	Dudina, Alexandra; Seichepine, Florent; Chen, Yihui; and Stettler, Alexander; Hierlemann, Andreas; and Frey, Urs Monolithic CMOS sensor platform featuring an array of 9’216 carbon-nanotube-sensor elements and low-noise, wide-bandwidth and wide-dynamic-range readout circuitry Journal Article Sensors and Actuators B: Chemical, 279 , pp. 255-266, 2019. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @article{Dudina2019, title = {Monolithic CMOS sensor platform featuring an array of 9’216 carbon-nanotube-sensor elements and low-noise, wide-bandwidth and wide-dynamic-range readout circuitry}, author = {Alexandra Dudina and Florent Seichepine and Yihui Chen and and Alexander Stettler and Andreas Hierlemann and and Urs Frey}, url = {https://www.sciencedirect.com/science/article/pii/S0925400518317672?via%3Dihub}, doi = {10.1016/j.snb.2018.10.004}, year = {2019}, date = {2019-01-15}, journal = {Sensors and Actuators B: Chemical}, volume = {279}, pages = {255-266}, abstract = {We present the design and characterization of a monolithic complementary metal–oxide–semiconductor (CMOS) biosensor platform comprising of a switch-matrix-based array of 9′216 carbon nanotube field-effect transistors (CNTFETs) and associated readout circuitry. The switch-matrix allows for flexible selection and simultaneous routing of 96 sensor elements to the corresponding readout channels. A low-noise, wide-bandwidth, wide-dynamic-range transimpedance continuous-time amplifier architecture has been implemented to facilitate resistance measurements in the range between 50 kΩ and 1 GΩ at a bandwidth of up to 1 MHz. The achieved accuracy of the resistance measurements over the whole range is 4%. The system has been successfully fabricated and tested and shows a noise performance equal to 2.14 pArms at a bandwidth of 1 kHz and 0.84 nArms at a bandwidth of 1 MHz. A batch integration of the CNTFETs has been achieved by using a dielectrophoresis (DEP)–based manipulation technique. The current-voltage curves of CNTFETs have been acquired, and the sensing capabilities of the system have been demonstrated by recording resistance changes of CNTFETs upon exposure to solutions with different pH values and different concentrations of NaCl. The smallest resolvable concentrations for the respective analytes were estimated to amount to 0.025 pH-units and 4 mM NaCl.}, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close We present the design and characterization of a monolithic complementary metal–oxide–semiconductor (CMOS) biosensor platform comprising of a switch-matrix-based array of 9′216 carbon nanotube field-effect transistors (CNTFETs) and associated readout circuitry. The switch-matrix allows for flexible selection and simultaneous routing of 96 sensor elements to the corresponding readout channels. A low-noise, wide-bandwidth, wide-dynamic-range transimpedance continuous-time amplifier architecture has been implemented to facilitate resistance measurements in the range between 50 kΩ and 1 GΩ at a bandwidth of up to 1 MHz. The achieved accuracy of the resistance measurements over the whole range is 4%. The system has been successfully fabricated and tested and shows a noise performance equal to 2.14 pArms at a bandwidth of 1 kHz and 0.84 nArms at a bandwidth of 1 MHz. A batch integration of the CNTFETs has been achieved by using a dielectrophoresis (DEP)–based manipulation technique. The current-voltage curves of CNTFETs have been acquired, and the sensing capabilities of the system have been demonstrated by recording resistance changes of CNTFETs upon exposure to solutions with different pH values and different concentrations of NaCl. The smallest resolvable concentrations for the respective analytes were estimated to amount to 0.025 pH-units and 4 mM NaCl. Close https://www.sciencedirect.com/science/article/pii/S0925400518317672?via%3Dihub doi:10.1016/j.snb.2018.10.004 Close
	Shadmani, Amir; Viswam, Vijay; Chen, Yihui; Bounik, Raziyeh; Dragas, Jelena; Radivojevic, Milos; Geissler, Sydney; Sitnikov, Sergey; Muller, Jan; Hierlemann, Andreas Stimulation and Artifact-suppression Techniques for in-vitro High-density Microelectrode Array Systems. Journal Article IEEE Transactions on Biomedical Engineering, 2019. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @article{Shadmani2019b, title = {Stimulation and Artifact-suppression Techniques for in-vitro High-density Microelectrode Array Systems.}, author = {Amir Shadmani and Vijay Viswam and Yihui Chen and Raziyeh Bounik and Jelena Dragas and Milos Radivojevic and Sydney Geissler and Sergey Sitnikov and Jan Muller and Andreas Hierlemann }, url = {https://ieeexplore.ieee.org/document/8599003}, doi = {10.1109/TBME.2018.2890530}, year = {2019}, date = {2019-01-01}, journal = {IEEE Transactions on Biomedical Engineering}, abstract = {We present novel voltage stimulation buffers with controlled output current, along with recording circuits featuring adjustable high-pass cut-off filtering to perform efficient stimulation while actively suppressing stimulation artifacts in high-density microelectrode arrays. Owing to the dense packing and close proximity of the electrodes in such systems, a stimulation through one electrode can cause large electrical artifacts on neighboring electrodes that easily saturate the corresponding recording amplifiers. To suppress such artifacts, the high-pass corner frequencies of all available 2048 recording channels can be raised from several Hz to several kHz by applying a "soft-reset" or pole-shifting technique. With the implemented artifact suppression technique, the saturation time of the recording circuits, connected to electrodes in immediate vicinity to the stimulation site, could be reduced to less than 150μs. For the stimulation buffer, we developed a circuit, which can operate in two modes: either control of only the stimulation voltage, or control of current and voltage during stimulation. The voltage-only controlled mode employs a local common-mode feedback operational transconductance amplifier with a near rail-to-rail input/output range, suitable for driving high capacitive loads. The current/voltage controlled mode is based on a positive current conveyor generating adjustable output currents, while its upper and lower output voltages are limited by two feedback loops. The current/voltage controlled circuit can generate stimulation pulses up to 30 μA with less than ±0.1% linearity error in the low-current mode, and up to 300 μA with less than ±0.2% linearity error in the high-current mode.}, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close We present novel voltage stimulation buffers with controlled output current, along with recording circuits featuring adjustable high-pass cut-off filtering to perform efficient stimulation while actively suppressing stimulation artifacts in high-density microelectrode arrays. Owing to the dense packing and close proximity of the electrodes in such systems, a stimulation through one electrode can cause large electrical artifacts on neighboring electrodes that easily saturate the corresponding recording amplifiers. To suppress such artifacts, the high-pass corner frequencies of all available 2048 recording channels can be raised from several Hz to several kHz by applying a "soft-reset" or pole-shifting technique. With the implemented artifact suppression technique, the saturation time of the recording circuits, connected to electrodes in immediate vicinity to the stimulation site, could be reduced to less than 150μs. For the stimulation buffer, we developed a circuit, which can operate in two modes: either control of only the stimulation voltage, or control of current and voltage during stimulation. The voltage-only controlled mode employs a local common-mode feedback operational transconductance amplifier with a near rail-to-rail input/output range, suitable for driving high capacitive loads. The current/voltage controlled mode is based on a positive current conveyor generating adjustable output currents, while its upper and lower output voltages are limited by two feedback loops. The current/voltage controlled circuit can generate stimulation pulses up to 30 μA with less than ±0.1% linearity error in the low-current mode, and up to 300 μA with less than ±0.2% linearity error in the high-current mode. Close https://ieeexplore.ieee.org/document/8599003 doi:10.1109/TBME.2018.2890530 Close
2018
	Bakkum, Douglas J; Obien, Marie Engelene J; Radivojevic, Milos; Jäckel, David; Frey, Urs; Takahashi, Hirokazu; Hierlemann, Andreas The Axon Initial Segment is the Dominant Contributor to the Neuron's Extracellular Electrical Potential Landscape Journal Article Advanced Biosystems, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @article{Bakkum2018b, title = {The Axon Initial Segment is the Dominant Contributor to the Neuron's Extracellular Electrical Potential Landscape}, author = {Douglas J. Bakkum and Marie Engelene J. Obien and Milos Radivojevic and David Jäckel and Urs Frey and Hirokazu Takahashi and Andreas Hierlemann}, url = {https://onlinelibrary.wiley.com/doi/full/10.1002/adbi.201800308}, doi = {10.1002/adbi.201800308}, year = {2018}, date = {2018-11-29}, journal = {Advanced Biosystems}, abstract = {Extracellular voltage fields, produced by a neuron's action potentials, provide a widely used means for studying neuronal and neuronal‐network function. The neuron's soma and dendrites are thought to drive the extracellular action potential (EAP) landscape, while the axon's contribution is usually considered less important. However, by recording voltages of single neurons in dissociated rat cortical cultures and Purkinje cells in acute mouse cerebellar slices through hundreds of densely packed electrodes, it is found, instead, that the axon initial segment dominates the measured EAP landscape, and, surprisingly, the soma only contributes to a minor extent. As expected, the recorded dominant signal has negative polarity (charge entering the cell) and initiates at the distal end. Interestingly, signals with positive polarity (charge exiting the cell) occur near some but not all dendritic branches and occur after a delay. Such basic knowledge about which neuronal compartments contribute to the extracellular voltage landscape is important for interpreting results from all electrical readout schemes. Finally, initiation of the electrical activity at the distal end of the axon initial segment (AIS) and subsequent spreading into the axon proper and backward through the proximal AIS toward the soma are confirmed. The corresponding extracellular waveforms across different neuronal compartments could be tracked.}, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close Extracellular voltage fields, produced by a neuron's action potentials, provide a widely used means for studying neuronal and neuronal‐network function. The neuron's soma and dendrites are thought to drive the extracellular action potential (EAP) landscape, while the axon's contribution is usually considered less important. However, by recording voltages of single neurons in dissociated rat cortical cultures and Purkinje cells in acute mouse cerebellar slices through hundreds of densely packed electrodes, it is found, instead, that the axon initial segment dominates the measured EAP landscape, and, surprisingly, the soma only contributes to a minor extent. As expected, the recorded dominant signal has negative polarity (charge entering the cell) and initiates at the distal end. Interestingly, signals with positive polarity (charge exiting the cell) occur near some but not all dendritic branches and occur after a delay. Such basic knowledge about which neuronal compartments contribute to the extracellular voltage landscape is important for interpreting results from all electrical readout schemes. Finally, initiation of the electrical activity at the distal end of the axon initial segment (AIS) and subsequent spreading into the axon proper and backward through the proximal AIS toward the soma are confirmed. The corresponding extracellular waveforms across different neuronal compartments could be tracked. Close https://onlinelibrary.wiley.com/doi/full/10.1002/adbi.201800308 doi:10.1002/adbi.201800308 Close
	Lewandowska, Marta K; Bogatikov, Evgenii; Hierlemann, Andreas; Punga, Anna Rostedt Long-term high-density extracellular recordings enable studies of muscle cell physiology and pathology Conference Contribution 700.13 , Society for Neuroscience (SfN) Meeting San Diego, CA, USA, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Physiology @conference{Lewandowska2018c, title = {Long-term high-density extracellular recordings enable studies of muscle cell physiology and pathology}, author = {Marta K. Lewandowska and Evgenii Bogatikov and Andreas Hierlemann and Anna Rostedt Punga}, url = {https://abstractsonline.com/pp8/#!/4649/presentation/24936}, year = {2018}, date = {2018-11-07}, volume = {Contribution 700.13}, address = {San Diego, CA, USA}, organization = {Society for Neuroscience (SfN) Meeting}, abstract = {Skeletal (voluntary) muscle is the most abundant tissue in the body, thus making it an important biomedical research subject. Studies of neuromuscular transmission, including disorders of defective ion channels or receptors in autoimmune or genetic neuromuscular disorders, require high spatial resolution and an ability to acquire repeated recordings over time in order to track pharmacological interventions. Preclinical techniques for studying diseases of neuromuscular transmission can be enhanced by physiologic ex vivo models of tissue-tissue and cell-cell interactions. We present a method, which we used to follow the development of primary skeletal muscle cells from myoblasts into mature contracting myofibers over more than two months. In contrast to most previous studies, the muscles do not detach from the surface but instead form functional networks between the myofibers, whose electrical signals we observed over the entire culturing period. Primary cultures of mouse myoblasts differentiated into contracting myofibers on a chip that contains an array of 26,400 platinum electrodes at a density of 3,265 electrodes per mm2. Our ability to track extracellular action potentials at subcellular resolution enables discovery of the origin of possible failure mechanisms in muscle diseases. This system in turn enables creation of a novel electrophysiological platform for establishing ex vivo disease models.}, keywords = {ETH-CMOS-MEA, Physiology}, pubstate = {published}, tppubtype = {conference} } Close Skeletal (voluntary) muscle is the most abundant tissue in the body, thus making it an important biomedical research subject. Studies of neuromuscular transmission, including disorders of defective ion channels or receptors in autoimmune or genetic neuromuscular disorders, require high spatial resolution and an ability to acquire repeated recordings over time in order to track pharmacological interventions. Preclinical techniques for studying diseases of neuromuscular transmission can be enhanced by physiologic ex vivo models of tissue-tissue and cell-cell interactions. We present a method, which we used to follow the development of primary skeletal muscle cells from myoblasts into mature contracting myofibers over more than two months. In contrast to most previous studies, the muscles do not detach from the surface but instead form functional networks between the myofibers, whose electrical signals we observed over the entire culturing period. Primary cultures of mouse myoblasts differentiated into contracting myofibers on a chip that contains an array of 26,400 platinum electrodes at a density of 3,265 electrodes per mm2. Our ability to track extracellular action potentials at subcellular resolution enables discovery of the origin of possible failure mechanisms in muscle diseases. This system in turn enables creation of a novel electrophysiological platform for establishing ex vivo disease models. Close https://abstractsonline.com/pp8/#!/4649/presentation/24936 Close
	Emmenegger, Vishalini; Bartram, Julian; Sitnikov, Sergey; Hierlemann, Andreas Investigating the analog modulation of action-potential waveforms in axonal arbors of cortical neurons using whole-cell patch-clamp recordings and high-density microelectrode arrays Conference Contribution 203.05 , Society for Neuroscience (SfN) Meeting, San Diego, CA, USA, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @conference{Emmenegger2018, title = {Investigating the analog modulation of action-potential waveforms in axonal arbors of cortical neurons using whole-cell patch-clamp recordings and high-density microelectrode arrays}, author = {Vishalini Emmenegger and Julian Bartram and Sergey Sitnikov and Andreas Hierlemann}, url = {https://abstractsonline.com/pp8/#!/4649/presentation/9323}, year = {2018}, date = {2018-11-04}, volume = {Contribution 203.05}, publisher = {Society for Neuroscience (SfN) Meeting}, address = {San Diego, CA, USA}, abstract = {Analog-digital facilitation (ADF) is a type of short-term plasticity, where the subthreshold membrane potential in the presynaptic element enhances the spike-evoked synaptic response. Most cases of ADF have been induced by long (0.3-10 s) subthreshold depolarization of the soma, while in few cases, transient (15-200 ms) hyperpolarization has been evoked immediately before the action potential (AP). In both cases, somatic membrane fluctuations modulate the biophysical properties of voltage-gated ion channels causing changes in the AP waveform, which result in larger release of neurotransmitters. However, it is still unknown, whether the modulation of the AP waveform changes with increasing distance from the soma and differs in different axonal arbors, and whether such modulation affects the velocity of AP propagation. Here, we used CMOS-based high-density microelectrode arrays (HD-MEA) with 26,400 microelectrodes, which enabled unprecedented high-resolution access to investigating axonal signaling at multiple sites simultaneously, thus providing in-depth information on the propagation of AP. The subthreshold depolarization and hyperpolarization of the presynaptic cell was performed using whole-cell patch-clamp recordings from cells in low-density cortical cultures, plated on a HD-MEA that allowed to trace the effects of such manipulations on AP propagation characteristics. Array-wide spike-triggered average signals were computed, and their spatiotemporal distribution was reconstructed. In order to study the changes in extracellular AP waveforms, we first induced pharmacological modulations using dendrotoxin and carbamazepine, which increased AP width and amplitude. As a next step, we evoked AP broadening and amplitude changes by subthreshold depolarization and hyperpolarization. We detected the extracellular AP waveforms directly under the soma and traced them throughout the axon during various time spans and for different holding potentials. We found that changes in AP propagation velocity were correlated to the detected AP broadening. Our preliminary data evidenced changes in AP waveforms with increasing distance from the soma along the axon, but further experiments on synaptically coupled neurons using paired recordings will be performed to better understand the influence of AP modulation on ADF. Information encoding in neuronal circuits is probably contingent on both, temporal spike patterns and spike waveforms. In the light of the latter being typically disregarded in computational models, the study of the analog modulation of AP waveforms will contribute to a better understanding of neuronal information processing.}, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {conference} } Close Analog-digital facilitation (ADF) is a type of short-term plasticity, where the subthreshold membrane potential in the presynaptic element enhances the spike-evoked synaptic response. Most cases of ADF have been induced by long (0.3-10 s) subthreshold depolarization of the soma, while in few cases, transient (15-200 ms) hyperpolarization has been evoked immediately before the action potential (AP). In both cases, somatic membrane fluctuations modulate the biophysical properties of voltage-gated ion channels causing changes in the AP waveform, which result in larger release of neurotransmitters. However, it is still unknown, whether the modulation of the AP waveform changes with increasing distance from the soma and differs in different axonal arbors, and whether such modulation affects the velocity of AP propagation. Here, we used CMOS-based high-density microelectrode arrays (HD-MEA) with 26,400 microelectrodes, which enabled unprecedented high-resolution access to investigating axonal signaling at multiple sites simultaneously, thus providing in-depth information on the propagation of AP. The subthreshold depolarization and hyperpolarization of the presynaptic cell was performed using whole-cell patch-clamp recordings from cells in low-density cortical cultures, plated on a HD-MEA that allowed to trace the effects of such manipulations on AP propagation characteristics. Array-wide spike-triggered average signals were computed, and their spatiotemporal distribution was reconstructed. In order to study the changes in extracellular AP waveforms, we first induced pharmacological modulations using dendrotoxin and carbamazepine, which increased AP width and amplitude. As a next step, we evoked AP broadening and amplitude changes by subthreshold depolarization and hyperpolarization. We detected the extracellular AP waveforms directly under the soma and traced them throughout the axon during various time spans and for different holding potentials. We found that changes in AP propagation velocity were correlated to the detected AP broadening. Our preliminary data evidenced changes in AP waveforms with increasing distance from the soma along the axon, but further experiments on synaptically coupled neurons using paired recordings will be performed to better understand the influence of AP modulation on ADF. Information encoding in neuronal circuits is probably contingent on both, temporal spike patterns and spike waveforms. In the light of the latter being typically disregarded in computational models, the study of the analog modulation of AP waveforms will contribute to a better understanding of neuronal information processing. Close https://abstractsonline.com/pp8/#!/4649/presentation/9323 Close
	Ronchi, Silvia; Fiscella, Michele; Marchetti, Camilla; Viswam, Vijay; Müller, Jan; Frey, Urs; Hierlemann, Andreas Single-neuron sub-cellular-resolution electrical stimulation with high-density microelectrode arrays Conference Contribution 174.05 , Society for Neuroscience (SfN) Meeting San Diego, CA, USA, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Stimulation @conference{Ronchi2018, title = {Single-neuron sub-cellular-resolution electrical stimulation with high-density microelectrode arrays}, author = {Silvia Ronchi and Michele Fiscella and Camilla Marchetti and Vijay Viswam and Jan Müller and Urs Frey and Andreas Hierlemann}, url = {https://abstractsonline.com/pp8/#!/4649/presentation/24382}, year = {2018}, date = {2018-11-04}, volume = {Contribution 174.05}, address = {San Diego, CA, USA}, organization = {Society for Neuroscience (SfN) Meeting}, abstract = {Non-invasive electrical stimulation is a consolidated technique to study and control neural activity in the brain and peripheral nervous system. It is used, e.g., for controlling Parkinson's disease or to induce sensation in paralyzed patients (Armenta Salas et al., 2018), as well as for attempts to restore vision (Fan et al., 2018; Grosberg et al., 2017) and hearing (Wilson & Dorman, 2008). A common requirement in electrical stimulation is the precise and controlled stimulation of individual targeted neurons. For achieving this purpose, it is necessary that electrodes can stimulate and record extracellular signals at sub-cellular resolution. Furthermore, it is important to design efficient stimulation pulses to be delivered to the neurons. In the present work we used an CMOS-based high-density microelectrode array (HD-MEA) (Ballini et al., 2014), featuring 26’400 bidirectional electrodes with a pitch of 17.5 µm, which was designed for in-vitro applications. This high-resolution was used to test electrical stimulation parameters in vitro, which then could potentially be adapted to elicit single-cell action potentials in vivo. In this work we used different stimulation parameters, such as waveforms, amplitudes and durations (Grosberg et al., 2017; Wagenaar, Pine, & Potter, 2004), using 5x9 µm² electrodes to target sub-cellular structures in single neurons. E-18 Wistar rat cortical neurons were stimulated at days-in-vitro 10, 15, 20 and 25 using randomized voltage and current stimulation modalities. Axon initial segments of individual neurons (Radivojevic et al., 2016) were targeted for stimulation, enabled by the HD-MEA device. We found that voltage biphasic anodic-cathodic waveforms were less efficient than biphasic cathodic-anodic waveforms in eliciting action potentials in a single neuron. Moreover, it was possible to detect action potentials directly at the cell soma, which ensured a reliable confirmation of successful neuron stimulation. Finally, HD-MEA technology enabled to elicit action potentials in single-neurons embedded in high-density cell cultures. The obtained results can be used to optimize in vivo single-cell targeting for stimulation and read-out.}, keywords = {ETH-CMOS-MEA, Stimulation}, pubstate = {published}, tppubtype = {conference} } Close Non-invasive electrical stimulation is a consolidated technique to study and control neural activity in the brain and peripheral nervous system. It is used, e.g., for controlling Parkinson's disease or to induce sensation in paralyzed patients (Armenta Salas et al., 2018), as well as for attempts to restore vision (Fan et al., 2018; Grosberg et al., 2017) and hearing (Wilson & Dorman, 2008). A common requirement in electrical stimulation is the precise and controlled stimulation of individual targeted neurons. For achieving this purpose, it is necessary that electrodes can stimulate and record extracellular signals at sub-cellular resolution. Furthermore, it is important to design efficient stimulation pulses to be delivered to the neurons. In the present work we used an CMOS-based high-density microelectrode array (HD-MEA) (Ballini et al., 2014), featuring 26’400 bidirectional electrodes with a pitch of 17.5 µm, which was designed for in-vitro applications. This high-resolution was used to test electrical stimulation parameters in vitro, which then could potentially be adapted to elicit single-cell action potentials in vivo. In this work we used different stimulation parameters, such as waveforms, amplitudes and durations (Grosberg et al., 2017; Wagenaar, Pine, & Potter, 2004), using 5x9 µm² electrodes to target sub-cellular structures in single neurons. E-18 Wistar rat cortical neurons were stimulated at days-in-vitro 10, 15, 20 and 25 using randomized voltage and current stimulation modalities. Axon initial segments of individual neurons (Radivojevic et al., 2016) were targeted for stimulation, enabled by the HD-MEA device. We found that voltage biphasic anodic-cathodic waveforms were less efficient than biphasic cathodic-anodic waveforms in eliciting action potentials in a single neuron. Moreover, it was possible to detect action potentials directly at the cell soma, which ensured a reliable confirmation of successful neuron stimulation. Finally, HD-MEA technology enabled to elicit action potentials in single-neurons embedded in high-density cell cultures. The obtained results can be used to optimize in vivo single-cell targeting for stimulation and read-out. Close https://abstractsonline.com/pp8/#!/4649/presentation/24382 Close
	Yuan, Xinyue; Emmenegger, Vishalini; Obien, Marie Engelene J; Hierlemann, Andreas; Frey, Urs Dual-Mode Microelectrode Array Featuring 20k Electrodes and High SNR for Extracellular Recording of Neural Networks Conference paper 6065 , IEEE Biomedical Circuits and Systems Conference (BioCAS) Cleveland, Ohio, USA, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @conference{Yuan2018b, title = {Dual-Mode Microelectrode Array Featuring 20k Electrodes and High SNR for Extracellular Recording of Neural Networks}, author = {Xinyue Yuan and Vishalini Emmenegger and Marie Engelene J. Obien and Andreas Hierlemann and Urs Frey}, url = {https://www.epapers.org/biocas2018/ESR/paper_details.php?PHPSESSID=ok076vdjtkiu7kett65d8hk0g0&paper_id=6056}, year = {2018}, date = {2018-10-17}, volume = {paper 6065}, address = {Cleveland, Ohio, USA}, organization = {IEEE Biomedical Circuits and Systems Conference (BioCAS)}, abstract = {In recent electrophysiological studies, CMOS-based high-density microelectrode arrays (HD-MEA) have been widely used for studies of both in-vitro and in-vivo neuronal signals and network behavior. Yet, an open issue in MEA design concerns the tradeoff between signal-to-noise ratio (SNR) and number of readout channels. Here we present a new HD-MEA design in 0.18 μm CMOS technology, consisting of 19,584 electrodes at a pitch of 18.0 μm. By combing two readout structures,namely active-pixel-sensor (APS) and switch-matrix (SM) on a single chip, the dual-mode HD-MEA is capable of recording simultaneously from the entire array and achieving high signal-to-noise-ratio recordings on a subset of electrodes. The APS readout circuits feature a noise level of 10.9 μVrms for the action potential band (300 Hz - 5 kHz), while the noise level for the switch-matrix readout is 3.1 μVrms. }, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {conference} } Close In recent electrophysiological studies, CMOS-based high-density microelectrode arrays (HD-MEA) have been widely used for studies of both in-vitro and in-vivo neuronal signals and network behavior. Yet, an open issue in MEA design concerns the tradeoff between signal-to-noise ratio (SNR) and number of readout channels. Here we present a new HD-MEA design in 0.18 μm CMOS technology, consisting of 19,584 electrodes at a pitch of 18.0 μm. By combing two readout structures,namely active-pixel-sensor (APS) and switch-matrix (SM) on a single chip, the dual-mode HD-MEA is capable of recording simultaneously from the entire array and achieving high signal-to-noise-ratio recordings on a subset of electrodes. The APS readout circuits feature a noise level of 10.9 μVrms for the action potential band (300 Hz - 5 kHz), while the noise level for the switch-matrix readout is 3.1 μVrms. Close https://www.epapers.org/biocas2018/ESR/paper_details.php?PHPSESSID=ok076vdjtkiu7[...] Close
	Lewandowska, Marta K; Bogatikov, Evgenii; Hierlemann, Andreas; Punga, Anna Rostedt Long-Term High-Density Extracellular Recordings Enable Studies of Muscle Cell Physiology Journal Article Frontiers in Physiology, 9 , 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Muscle @article{Lewandowska2018cb, title = {Long-Term High-Density Extracellular Recordings Enable Studies of Muscle Cell Physiology }, author = {Marta K. Lewandowska and Evgenii Bogatikov and Andreas Hierlemann and Anna Rostedt Punga}, url = {https://www.frontiersin.org/article/10.3389/fphys.2018.01424 }, doi = {10.3389/fphys.2018.01424}, year = {2018}, date = {2018-10-09}, journal = {Frontiers in Physiology}, volume = {9}, abstract = {Skeletal (voluntary) muscle is the most abundant tissue in the body, thus making it an important biomedical research subject. Studies of neuromuscular transmission, including disorders of ion channels or receptors in autoimmune or genetic neuromuscular disorders, require high-spatial-resolution measurement techniques and an ability to acquire repeated recordings over time in order to track pharmacological interventions. Preclinical techniques for studying diseases of neuromuscular transmission can be enhanced by physiologic ex vivo models of tissue-tissue and cell-cell interactions. Here, we present a method, which allows tracking the development of primary skeletal muscle cells from myoblasts into mature contracting myotubes over more than 2 months. In contrast to most previous studies, the myotubes did not detach from the surface but instead formed functional networks between the myotubes, whose electrical signals were observed over the entire culturing period. Primary cultures of mouse myoblasts differentiated into contracting myotubes on a chip that contained an array of 26,400 platinum electrodes at a density of 3,265 electrodes per mm2. Our ability to track extracellular action potentials at subcellular resolution enabled study of skeletal muscle development and kinetics, modes of spiking and spatio-temporal relationships between muscles. The developed system in turn enables creation of a novel electrophysiological platform for establishing ex vivo disease models. }, keywords = {ETH-CMOS-MEA, Muscle}, pubstate = {published}, tppubtype = {article} } Close Skeletal (voluntary) muscle is the most abundant tissue in the body, thus making it an important biomedical research subject. Studies of neuromuscular transmission, including disorders of ion channels or receptors in autoimmune or genetic neuromuscular disorders, require high-spatial-resolution measurement techniques and an ability to acquire repeated recordings over time in order to track pharmacological interventions. Preclinical techniques for studying diseases of neuromuscular transmission can be enhanced by physiologic ex vivo models of tissue-tissue and cell-cell interactions. Here, we present a method, which allows tracking the development of primary skeletal muscle cells from myoblasts into mature contracting myotubes over more than 2 months. In contrast to most previous studies, the myotubes did not detach from the surface but instead formed functional networks between the myotubes, whose electrical signals were observed over the entire culturing period. Primary cultures of mouse myoblasts differentiated into contracting myotubes on a chip that contained an array of 26,400 platinum electrodes at a density of 3,265 electrodes per mm2. Our ability to track extracellular action potentials at subcellular resolution enabled study of skeletal muscle development and kinetics, modes of spiking and spatio-temporal relationships between muscles. The developed system in turn enables creation of a novel electrophysiological platform for establishing ex vivo disease models. Close https://www.frontiersin.org/article/10.3389/fphys.2018.01424 doi:10.3389/fphys.2018.01424 Close
	Ronchi, Silvia; Fiscella, Michele; Muller, Jan; Viswam, Vijay; Frey, Urs; Hierlemann, Andreas Single-cell electrical stimulation with CMOS-based high-density microelectrode arrays Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Stimulation @conference{Ronchi2018b, title = {Single-cell electrical stimulation with CMOS-based high-density microelectrode arrays}, author = {Silvia Ronchi and Michele Fiscella and Jan Muller and Vijay Viswam and Urs Frey and Andreas Hierlemann}, url = {https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00086/event_abstract}, doi = {10.3389/conf.fncel.2018.38.00086}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {The main goal of this work was to explore electrical stimulation parameters that reproducibly and precisely elicit action potentials in single neurons (Wagenaar et al. 2004). We compared voltage and current modalities’ and their efficacy in activating single neurons; we also studied the related stimulation artifacts. For our studies, we used a CMOS-based MEA featuring 26400 electrodes at 17.5 µm pitch (Ballini et al. 2014). }, keywords = {ETH-CMOS-MEA, Stimulation}, pubstate = {published}, tppubtype = {conference} } Close The main goal of this work was to explore electrical stimulation parameters that reproducibly and precisely elicit action potentials in single neurons (Wagenaar et al. 2004). We compared voltage and current modalities’ and their efficacy in activating single neurons; we also studied the related stimulation artifacts. For our studies, we used a CMOS-based MEA featuring 26400 electrodes at 17.5 µm pitch (Ballini et al. 2014). Close https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00086/event_abstract doi:10.3389/conf.fncel.2018.38.00086 Close
	Obien, Marie Engelene J; Zorzi, Giulio; Fiscella, Michele; Leary, Noelle; Hierlemann, Andreas Comparison of axonal-conduction velocity in developing primary cells and human iPSC-derived neurons Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MaxOne @conference{Obien2018, title = {Comparison of axonal-conduction velocity in developing primary cells and human iPSC-derived neurons}, author = {Marie Engelene J. Obien and Giulio Zorzi and Michele Fiscella and Noelle Leary and Andreas Hierlemann}, url = {https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00095/event_abstract}, doi = {10.3389/conf.fncel.2018.38.00095}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {Neurons communicate through action potentials propagating along axons. In developing cell cultures, axonal arbor outgrowth indicates the formation of synaptic connections between neurons, which form networks. As axons regulate the transfer of information, we hypothesize that axonal conduction characteristics, e.g., axonal action potential amplitude and propagation velocity, may be indicative of the maturation state of cells and the strength of interneuronal connections.}, keywords = {ETH-CMOS-MEA, MaxOne}, pubstate = {published}, tppubtype = {conference} } Close Neurons communicate through action potentials propagating along axons. In developing cell cultures, axonal arbor outgrowth indicates the formation of synaptic connections between neurons, which form networks. As axons regulate the transfer of information, we hypothesize that axonal conduction characteristics, e.g., axonal action potential amplitude and propagation velocity, may be indicative of the maturation state of cells and the strength of interneuronal connections. Close https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00095/event_abstract doi:10.3389/conf.fncel.2018.38.00095 Close
	Zorzi, Giulio; Obien, Marie Engelene J; Fiscella, Michele; Leary, Noelle; Hierlemann, Andreas Automatic extraction of axonal arbor morphology applied to h-iPSC-derived neurons Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MaxOne @conference{Zorzi2018, title = {Automatic extraction of axonal arbor morphology applied to h-iPSC-derived neurons}, author = {Giulio Zorzi and Marie Engelene J. Obien and Michele Fiscella and Noelle Leary and Andreas Hierlemann}, url = {https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00049/event_abstract}, doi = {10.3389/conf.fncel.2018.38.00049}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {Neurons derived from human induced pluripotent stem cells (h-iPSCs) offer tremendous opportunities to investigate the mechanisms involved in brain function and to model neurodegenerative diseases. Analyzing the behavior of h-iPSC-derived neurons that represent the phenotypes of human neurological disorders paves the way for the development of physiologically-relevant models and assays for drug discovery. In this framework, we utilize a CMOS-based high-density microelectrode array (HD-MEA, MaxWell Biosystems) to investigate h-iPSC neurons at sub-cellular resolution. Recording extracellular action potentials (EAPs or spikes) of cultured neurons through microelectrode arrays (MEAs) is a well-established technique for extracting valuable features of neuronal function and network connectivity (Obien et al., Frontiers in Neuroscience, 2015). }, keywords = {ETH-CMOS-MEA, MaxOne}, pubstate = {published}, tppubtype = {conference} } Close Neurons derived from human induced pluripotent stem cells (h-iPSCs) offer tremendous opportunities to investigate the mechanisms involved in brain function and to model neurodegenerative diseases. Analyzing the behavior of h-iPSC-derived neurons that represent the phenotypes of human neurological disorders paves the way for the development of physiologically-relevant models and assays for drug discovery. In this framework, we utilize a CMOS-based high-density microelectrode array (HD-MEA, MaxWell Biosystems) to investigate h-iPSC neurons at sub-cellular resolution. Recording extracellular action potentials (EAPs or spikes) of cultured neurons through microelectrode arrays (MEAs) is a well-established technique for extracting valuable features of neuronal function and network connectivity (Obien et al., Frontiers in Neuroscience, 2015). Close https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00049/event_abstract doi:10.3389/conf.fncel.2018.38.00049 Close
	Bounik, Raziyeh; Gusmaroli, Massimiliano; Viswam, Vijay; Modena, Mario M; Hierlemann, Andreas COMSOL modeling of an integrated impedance sensor in a hanging-drop platform Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Microtissue @conference{Bounik2018, title = {COMSOL modeling of an integrated impedance sensor in a hanging-drop platform}, author = {Raziyeh Bounik and Massimiliano Gusmaroli and Vijay Viswam and Mario M. Modena and Andreas Hierlemann}, url = {https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00083/event_abstract}, doi = {10.3389/conf.fncel.2018.38.00083}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {Traditional dish-based, two-dimensional cell cultures have limited prediction capability for drug testing, whereas three-dimensional spherical microtissues (spheroids) and organoids much more accurately replicate physiological conditions of cells in the respective tissue [1,2]. Such spheroids can be formed and cultured in microphysiological multi-tissue formats by using the hanging-drop technology as depicted in Fig. 1 [3]. Like most other microfluidic platforms, the hanging-drop platform still requires a microscope for visual inspection and considerable time for doing off-line measurements, as the spheroids/media have to be harvested from the microfluidic device for labeling and chemical analysis. It would be beneficial to have an integrated on-line multi-functional sensor as an additional readout, located directly at the tissue sites in the hanging-drop platform, so that measurements can be performed in situ and without harvesting medium or the tissue and without interrupting the overall culturing process. }, keywords = {ETH-CMOS-MEA, Microtissue}, pubstate = {published}, tppubtype = {conference} } Close Traditional dish-based, two-dimensional cell cultures have limited prediction capability for drug testing, whereas three-dimensional spherical microtissues (spheroids) and organoids much more accurately replicate physiological conditions of cells in the respective tissue [1,2]. Such spheroids can be formed and cultured in microphysiological multi-tissue formats by using the hanging-drop technology as depicted in Fig. 1 [3]. Like most other microfluidic platforms, the hanging-drop platform still requires a microscope for visual inspection and considerable time for doing off-line measurements, as the spheroids/media have to be harvested from the microfluidic device for labeling and chemical analysis. It would be beneficial to have an integrated on-line multi-functional sensor as an additional readout, located directly at the tissue sites in the hanging-drop platform, so that measurements can be performed in situ and without harvesting medium or the tissue and without interrupting the overall culturing process. Close https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00083/event_abstract doi:10.3389/conf.fncel.2018.38.00083 Close
	Yuan, Xinyue; Hierlemann, Andreas; Frey, Urs Dual-mode Microelectrode Array with 20k-electrodes and High SNR for High-Throughput Extracellular Recording and Stimulation Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Stimulation @conference{Yuan2018, title = {Dual-mode Microelectrode Array with 20k-electrodes and High SNR for High-Throughput Extracellular Recording and Stimulation}, author = {Xinyue Yuan and Andreas Hierlemann and Urs Frey}, url = {https://https://www.frontiersin.org/Community/AbstractDetails.aspx?ABS_DOI=10.3389/conf.fncel.2018.38.00088&eid=5473&sname=MEA_Meeting_2018_%7C_11th_International_Meeting_on_Substrate_Integrated_Microelectrode_Arrays}, doi = {10.3389/conf.fncel.2018.38.00088}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {Recording and analysis of neuronal signals can provide much insight into how neurons process information and communicate with each other. Recent advancements of microelectrode-array (MEA) technology provide unprecedented means to study neuronal signals and network behavior in in vitro and in vivo applications [1], [2]. The trade-off between noise performance, power consumption and electrode density, however, remains a major challenge in MEA design. To balance this tradeoff, we designed a Dual-mode (DM) MEA that combines two major types of readout schemes, i.e., the active-pixel-sensor (APS) and switch-matrix (SM) schemes, in order to achieve high electrode density and high signal-to-noise ratio (SNR) at the same time. Based on a previous prototype [3], the new DM-MEA has shown to be a useful tool for in-vitro neuroscience studies, especially for network studies}, keywords = {ETH-CMOS-MEA, Stimulation}, pubstate = {published}, tppubtype = {conference} } Close Recording and analysis of neuronal signals can provide much insight into how neurons process information and communicate with each other. Recent advancements of microelectrode-array (MEA) technology provide unprecedented means to study neuronal signals and network behavior in in vitro and in vivo applications [1], [2]. The trade-off between noise performance, power consumption and electrode density, however, remains a major challenge in MEA design. To balance this tradeoff, we designed a Dual-mode (DM) MEA that combines two major types of readout schemes, i.e., the active-pixel-sensor (APS) and switch-matrix (SM) schemes, in order to achieve high electrode density and high signal-to-noise ratio (SNR) at the same time. Based on a previous prototype [3], the new DM-MEA has shown to be a useful tool for in-vitro neuroscience studies, especially for network studies Close https://https://www.frontiersin.org/Community/AbstractDetails.aspx?ABS_DOI=10.33[...] doi:10.3389/conf.fncel.2018.38.00088 Close
	Bakkum Douglas J; Radivojevic, Milos; Obien Marie Engelene; Jaeckel David; Frey Urs; Takahashi Hirokazu; Hierlemann Andreas The axon initial segment drives the neuron's extracellular action potential Journal Article bioRxiv, pp. 1-30, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @article{Bakkum2018, title = {The axon initial segment drives the neuron's extracellular action potential}, author = {Bakkum, Douglas J; Radivojevic, Milos; Obien, Marie Engelene; Jaeckel, David; Frey, Urs; Takahashi, Hirokazu; Hierlemann, Andreas }, url = {https://www.biorxiv.org/content/early/2018/02/16/266734}, doi = {10.1101/266734 }, year = {2018}, date = {2018-02-16}, journal = {bioRxiv}, pages = {1-30}, abstract = {Extracellular voltage fields produced by a neuron's action potentials provide a primary means for studying neuron function, yet their biophysical sources remain ambiguous. The neuron's soma and dendrites are thought to drive the extracellular action potential (EAP), while the axon is usually ignored. However, by recording voltages of single neurons in dissociated rat cortical cultures and Purkinje cells in acute mouse cerebellar slices at hundreds of sites, we find instead that the axon initial segment dominates the EAP, and, surprisingly, the soma shows little or no influence. As expected, this signal has negative polarity (charge entering the cell) and initiates at the distal end. Interestingly, signals with positive polarity (charge exiting the cell) occur near some but not all dendritic branches and occur after a delay. Such basic knowledge about which neuronal compartments contribute to the extracellular voltage field is important for interpreting results from all electrical readout schemes. Moreover, this finding shows that changes in the AIS position and function can be observed in high spatiotemporal detail by means of high-density extracellular electrophysiology.}, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close Extracellular voltage fields produced by a neuron's action potentials provide a primary means for studying neuron function, yet their biophysical sources remain ambiguous. The neuron's soma and dendrites are thought to drive the extracellular action potential (EAP), while the axon is usually ignored. However, by recording voltages of single neurons in dissociated rat cortical cultures and Purkinje cells in acute mouse cerebellar slices at hundreds of sites, we find instead that the axon initial segment dominates the EAP, and, surprisingly, the soma shows little or no influence. As expected, this signal has negative polarity (charge entering the cell) and initiates at the distal end. Interestingly, signals with positive polarity (charge exiting the cell) occur near some but not all dendritic branches and occur after a delay. Such basic knowledge about which neuronal compartments contribute to the extracellular voltage field is important for interpreting results from all electrical readout schemes. Moreover, this finding shows that changes in the AIS position and function can be observed in high spatiotemporal detail by means of high-density extracellular electrophysiology. Close https://www.biorxiv.org/content/early/2018/02/16/266734 doi:10.1101/266734 Close
2017
	Radivojevic, Milos; Franke, Felix; Altermatt, Michael; Müller, Jan; Hierlemann, Andreas; Bakkum, Douglas J Tracking individual action potentials throughout mammalian axonal arbors Journal Article eLife, 6 , pp. 1-23, 2017, ISSN: 2050-084X. Abstract \| Links \| BibTeX \| Tags: Data Analysis, ETH-CMOS-MEA, Neuronal Networks, Stimulation @article{Radivojevic2017, title = {Tracking individual action potentials throughout mammalian axonal arbors}, author = {Milos Radivojevic and Felix Franke and Michael Altermatt and Jan Müller and Andreas Hierlemann and Douglas J Bakkum}, url = {https://elifesciences.org/articles/30198}, doi = {10.7554/eLife.30198}, issn = {2050-084X}, year = {2017}, date = {2017-10-09}, journal = {eLife}, volume = {6}, pages = {1-23}, abstract = {Axons are neuronal processes specialized for conduction of action potentials (APs). The timing and temporal precision of APs when they reach each of the synapses are fundamentally important for information processing in the brain. Due to small diameters of axons, direct recording of single AP transmission is challenging. Consequently, most knowledge about axonal conductance derives from modeling studies or indirect measurements. We demonstrate a method to noninvasively and directly record individual APs propagating along millimeter-length axonal arbors in cortical cultures with hundreds of microelectrodes at microsecond temporal resolution. We find that cortical axons conduct single APs with high temporal precision (~100 µs arrival time jitter per mm length) and reliability: in more than 8,000,000 recorded APs, we did not observe any conduction or branch-point failures. Upon high-frequency stimulation at 100 Hz, successive became slower, and their arrival time precision decreased by 20% and 12% for the 100th AP, respectively.}, keywords = {Data Analysis, ETH-CMOS-MEA, Neuronal Networks, Stimulation}, pubstate = {published}, tppubtype = {article} } Close Axons are neuronal processes specialized for conduction of action potentials (APs). The timing and temporal precision of APs when they reach each of the synapses are fundamentally important for information processing in the brain. Due to small diameters of axons, direct recording of single AP transmission is challenging. Consequently, most knowledge about axonal conductance derives from modeling studies or indirect measurements. We demonstrate a method to noninvasively and directly record individual APs propagating along millimeter-length axonal arbors in cortical cultures with hundreds of microelectrodes at microsecond temporal resolution. We find that cortical axons conduct single APs with high temporal precision (~100 µs arrival time jitter per mm length) and reliability: in more than 8,000,000 recorded APs, we did not observe any conduction or branch-point failures. Upon high-frequency stimulation at 100 Hz, successive became slower, and their arrival time precision decreased by 20% and 12% for the 100th AP, respectively. Close https://elifesciences.org/articles/30198 doi:10.7554/eLife.30198 Close
	Viswam, Vijay; Bounik, Raziyeh; Shadmani, Amir; Dragas, Jelena; Obien, Marie Engelene J; Muller, Jan; Chen, Yihui; Hierlemann, Andreas High-density Mapping of Brain Slices Using a Large Multi-functional High-density CMOS Microelectrode Array System Conference 19th International Conference on Solid-State Sensors, Actuators and Microsystems (TRANSDUCERS) Kaohsiung, Taiwan, 2017, ISSN: 2167-0021. Abstract \| Links \| BibTeX \| Tags: Brain Slice, ETH-CMOS-MEA, HD-MEA @conference{Viswam2017b, title = {High-density Mapping of Brain Slices Using a Large Multi-functional High-density CMOS Microelectrode Array System}, author = {Vijay Viswam and Raziyeh Bounik and Amir Shadmani and Jelena Dragas and Marie Engelene J. Obien and Jan Muller and Yihui Chen and Andreas Hierlemann }, url = {https://ieeexplore.ieee.org/abstract/document/7994006}, doi = {10.1109/TRANSDUCERS.2017.7994006}, issn = {2167-0021}, year = {2017}, date = {2017-06-18}, pages = {135-138}, address = {Kaohsiung, Taiwan}, organization = {19th International Conference on Solid-State Sensors, Actuators and Microsystems (TRANSDUCERS)}, abstract = {We present a CMOS-based high-density microelectrode array (HD-MEA) system that enables high-density mapping of brain slices in-vitro with multiple readout modalities. The 4.48×2.43 mm 2 array consists of 59,760 micro-electrodes at 13.5 μm pitch (5487 electrodes/mm 2 ). The overall system features 2048 action-potential, 32 local-field-potential and 32 current recording channels, 32 impedance-measurement and 28 neurotransmitter-detection channels and 16 voltage/current stimulation channels. The system enables real-time and label-free monitoring of position, size, morphology and electrical activity of brain slices.}, keywords = {Brain Slice, ETH-CMOS-MEA, HD-MEA}, pubstate = {published}, tppubtype = {conference} } Close We present a CMOS-based high-density microelectrode array (HD-MEA) system that enables high-density mapping of brain slices in-vitro with multiple readout modalities. The 4.48×2.43 mm 2 array consists of 59,760 micro-electrodes at 13.5 μm pitch (5487 electrodes/mm 2 ). The overall system features 2048 action-potential, 32 local-field-potential and 32 current recording channels, 32 impedance-measurement and 28 neurotransmitter-detection channels and 16 voltage/current stimulation channels. The system enables real-time and label-free monitoring of position, size, morphology and electrical activity of brain slices. Close https://ieeexplore.ieee.org/abstract/document/7994006 doi:10.1109/TRANSDUCERS.2017.7994006 Close
	Bullmann Torsten; Radivojevic, Milos; Huber Stefan Deligkaris Kosmas; Hierlemann Andreas; Frey Urs T: Network Analysis Of High-Density Microelectrode Recordings Journal Article bioRxiv , (139436), pp. 1-23, 2017. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @article{Bullmann2017, title = {Network Analysis Of High-Density Microelectrode Recordings}, author = {Bullmann, Torsten; Radivojevic, Milos; Huber, Stefan T: Deligkaris, Kosmas; Hierlemann, Andreas; Frey, Urs }, url = {https://www.biorxiv.org/content/early/2017/05/18/139436 }, doi = {10.1101/139436}, year = {2017}, date = {2017-05-18}, journal = {bioRxiv }, number = {139436}, pages = {1-23}, abstract = {Extracellular voltage fields produced by a neuron's action potentials provide a primary means for studying neuron function, yet their biophysical sources remain ambiguous. The neuron's soma and dendrites are thought to drive the extracellular action potential (EAP), while the axon is usually ignored. However, by recording voltages of single neurons in dissociated rat cortical cultures and Purkinje cells in acute mouse cerebellar slices at hundreds of sites, we find instead that the axon initial segment dominates the EAP, and, surprisingly, the soma shows little or no influence. As expected, this signal has negative polarity (charge entering the cell) and initiates at the distal end. Interestingly, signals with positive polarity (charge exiting the cell) occur near some but not all dendritic branches and occur after a delay. Such basic knowledge about which neuronal compartments contribute to the extracellular voltage field is important for interpreting results from all electrical readout schemes. Moreover, this finding shows that changes in the AIS position and function can be observed in high spatiotemporal detail by means of high-density extracellular electrophysiology.}, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close Extracellular voltage fields produced by a neuron's action potentials provide a primary means for studying neuron function, yet their biophysical sources remain ambiguous. The neuron's soma and dendrites are thought to drive the extracellular action potential (EAP), while the axon is usually ignored. However, by recording voltages of single neurons in dissociated rat cortical cultures and Purkinje cells in acute mouse cerebellar slices at hundreds of sites, we find instead that the axon initial segment dominates the EAP, and, surprisingly, the soma shows little or no influence. As expected, this signal has negative polarity (charge entering the cell) and initiates at the distal end. Interestingly, signals with positive polarity (charge exiting the cell) occur near some but not all dendritic branches and occur after a delay. Such basic knowledge about which neuronal compartments contribute to the extracellular voltage field is important for interpreting results from all electrical readout schemes. Moreover, this finding shows that changes in the AIS position and function can be observed in high spatiotemporal detail by means of high-density extracellular electrophysiology. Close https://www.biorxiv.org/content/early/2017/05/18/139436 doi:10.1101/139436 Close
	Dragas, Jelena; Viswam, Vijay; Shadmani, Amir; Chen, Yihui; Bounik, Raziyeh; Stettler, Alexander; Radivojevic, Milos; Geissler, Sydney; Obien, Marie Engelene J; Müller, Jan; Hierlemann, Andreas A Multi-Functional Microelectrode Array Featuring 59760 Electrodes, 2048 Electrophysiology Channels, Stimulation, Impedance Measurement and Neurotransmitter Detection Channels Journal Article IEEE journal of solid-state circuits, 52 (6), pp. 1576-1590, 2017, ISSN: 0018-9200. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MEA Technology @article{Dragas2017, title = {A Multi-Functional Microelectrode Array Featuring 59760 Electrodes, 2048 Electrophysiology Channels, Stimulation, Impedance Measurement and Neurotransmitter Detection Channels}, author = {Jelena Dragas and Vijay Viswam and Amir Shadmani and Yihui Chen and Raziyeh Bounik and Alexander Stettler and Milos Radivojevic and Sydney Geissler and Marie Engelene J Obien and Jan Müller and Andreas Hierlemann}, url = {http://ieeexplore.ieee.org/document/7913669/}, doi = {10.1109/JSSC.2017.2686580}, issn = {0018-9200}, year = {2017}, date = {2017-04-27}, journal = {IEEE journal of solid-state circuits}, volume = {52}, number = {6}, pages = {1576-1590}, abstract = {Biological cells are characterized by highly complex phenomena and processes that are, to a great extent, interdependent. To gain detailed insights, devices designed to study cellular phenomena need to enable tracking and manipulation of multiple cell parameters in parallel; they have to provide high signal quality and high spatiotemporal resolution. To this end, we have developed a CMOS-based microelectrode array system that integrates six measurement and stimulation functions, the largest number to date. Moreover, the system features the largest active electrode array area to date (4.48×2.43 mm(2)) to accommodate 59,760 electrodes, while its power consumption, noise characteristics, and spatial resolution (13.5 mum electrode pitch) are comparable to the best state-of-the-art devices. The system includes: 2,048 action-potential (AP, bandwidth: 300 Hz to 10 kHz) recording units, 32 local-field-potential (LFP, bandwidth: 1 Hz to 300 Hz) recording units, 32 current recording units, 32 impedance measurement units, and 28 neurotransmitter detection units, in addition to the 16 dual-mode voltage-only or current/voltage-controlled stimulation units. The electrode array architecture is based on a switch matrix, which allows for connecting any measurement/stimulation unit to any electrode in the array and for performing different measurement/stimulation functions in parallel.}, keywords = {ETH-CMOS-MEA, MEA Technology}, pubstate = {published}, tppubtype = {article} } Close Biological cells are characterized by highly complex phenomena and processes that are, to a great extent, interdependent. To gain detailed insights, devices designed to study cellular phenomena need to enable tracking and manipulation of multiple cell parameters in parallel; they have to provide high signal quality and high spatiotemporal resolution. To this end, we have developed a CMOS-based microelectrode array system that integrates six measurement and stimulation functions, the largest number to date. Moreover, the system features the largest active electrode array area to date (4.48×2.43 mm(2)) to accommodate 59,760 electrodes, while its power consumption, noise characteristics, and spatial resolution (13.5 mum electrode pitch) are comparable to the best state-of-the-art devices. The system includes: 2,048 action-potential (AP, bandwidth: 300 Hz to 10 kHz) recording units, 32 local-field-potential (LFP, bandwidth: 1 Hz to 300 Hz) recording units, 32 current recording units, 32 impedance measurement units, and 28 neurotransmitter detection units, in addition to the 16 dual-mode voltage-only or current/voltage-controlled stimulation units. The electrode array architecture is based on a switch matrix, which allows for connecting any measurement/stimulation unit to any electrode in the array and for performing different measurement/stimulation functions in parallel. Close http://ieeexplore.ieee.org/document/7913669/ doi:10.1109/JSSC.2017.2686580 Close
	Jäckel, David; Bakkum, Douglas J; Russell, Thomas L; Müller, Jan; Radivojevic, Milos; Frey, Urs; Franke, Felix; Hierlemann, Andreas Combination of High-density Microelectrode Array and Patch Clamp Recordings to Enable Studies of Multisynaptic Integration Journal Article Scientific Reports, 7 (1), pp. 978, 2017, ISSN: 2045-2322. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks @article{Jackel2017, title = {Combination of High-density Microelectrode Array and Patch Clamp Recordings to Enable Studies of Multisynaptic Integration}, author = {David Jäckel and Douglas J Bakkum and Thomas L Russell and Jan Müller and Milos Radivojevic and Urs Frey and Felix Franke and Andreas Hierlemann}, url = {http://www.nature.com/articles/s41598-017-00981-4}, doi = {10.1038/s41598-017-00981-4}, issn = {2045-2322}, year = {2017}, date = {2017-04-20}, journal = {Scientific Reports}, volume = {7}, number = {1}, pages = {978}, abstract = {We present a novel, all-electric approach to record and to precisely control the activity of tens of individual presynaptic neurons. The method allows for parallel mapping of the efficacy of multiple synapses and of the resulting dynamics of postsynaptic neurons in a cortical culture. For the measurements, we combine an extracellular high-density microelectrode array, featuring 11'000 electrodes for extracellular recording and stimulation, with intracellular patch-clamp recording. We are able to identify the contributions of individual presynaptic neurons - including inhibitory and excitatory synaptic inputs - to postsynaptic potentials, which enables us to study dendritic integration. Since the electrical stimuli can be controlled at microsecond resolution, our method enables to evoke action potentials at tens of presynaptic cells in precisely orchestrated sequences of high reliability and minimum jitter. We demonstrate the potential of this method by evoking short- and long-term synaptic plasticity through manipulation of multiple synaptic inputs to a specific neuron.}, keywords = {ETH-CMOS-MEA, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close We present a novel, all-electric approach to record and to precisely control the activity of tens of individual presynaptic neurons. The method allows for parallel mapping of the efficacy of multiple synapses and of the resulting dynamics of postsynaptic neurons in a cortical culture. For the measurements, we combine an extracellular high-density microelectrode array, featuring 11'000 electrodes for extracellular recording and stimulation, with intracellular patch-clamp recording. We are able to identify the contributions of individual presynaptic neurons - including inhibitory and excitatory synaptic inputs - to postsynaptic potentials, which enables us to study dendritic integration. Since the electrical stimuli can be controlled at microsecond resolution, our method enables to evoke action potentials at tens of presynaptic cells in precisely orchestrated sequences of high reliability and minimum jitter. We demonstrate the potential of this method by evoking short- and long-term synaptic plasticity through manipulation of multiple synaptic inputs to a specific neuron. Close http://www.nature.com/articles/s41598-017-00981-4 doi:10.1038/s41598-017-00981-4 Close
	Seichepine, Florent; Rothe, Jorg; Dudina, Alexandra; Hierlemann, Andreas; Frey, Urs Dielectrophoresis‐Assisted Integration of 1024 Carbon Nanotube Sensors into a CMOS Microsystem Journal Article Advanced Materials, 29 (17), 2017. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @article{Seichepine2017, title = {Dielectrophoresis‐Assisted Integration of 1024 Carbon Nanotube Sensors into a CMOS Microsystem}, author = {Florent Seichepine and Jorg Rothe and Alexandra Dudina and Andreas Hierlemann and Urs Frey}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/adma.201606852}, doi = {10.1002/adma.201606852}, year = {2017}, date = {2017-03-15}, journal = {Advanced Materials}, volume = {29}, number = {17}, abstract = {Carbon‐nanotube (CNT)‐based sensors offer the potential to detect single‐molecule events and picomolar analyte concentrations. An important step toward applications of such nanosensors is their integration in large arrays. The availability of large arrays would enable multiplexed and parallel sensing, and the simultaneously obtained sensor signals would facilitate statistical analysis. A reliable method to fabricate an array of 1024 CNT‐based sensors on a fully processed complementary‐metal‐oxide‐semiconductor microsystem is presented. A high‐yield process for the deposition of CNTs from a suspension by means of liquid‐coupled floating‐electrode dielectrophoresis (DEP), which yielded 80% of the sensor devices featuring between one and five CNTs, is developed. The mechanism of floating‐electrode DEP on full arrays and individual devices to understand its self‐limiting behavior is studied. The resistance distributions across the array of CNT devices with respect to different DEP parameters are characterized. The CNT devices are then operated as liquid‐gated CNT field‐effect‐transistors (LG‐CNTFET) in liquid environment. Current dependency to the gate voltage of up to two orders of magnitude is recorded. Finally, the sensors are validated by studying the pH dependency of the LG‐CNTFET conductance and it is demonstrated that 73% of the CNT sensors of a given microsystem show a resistance decrease upon increasing the pH value.}, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close Carbon‐nanotube (CNT)‐based sensors offer the potential to detect single‐molecule events and picomolar analyte concentrations. An important step toward applications of such nanosensors is their integration in large arrays. The availability of large arrays would enable multiplexed and parallel sensing, and the simultaneously obtained sensor signals would facilitate statistical analysis. A reliable method to fabricate an array of 1024 CNT‐based sensors on a fully processed complementary‐metal‐oxide‐semiconductor microsystem is presented. A high‐yield process for the deposition of CNTs from a suspension by means of liquid‐coupled floating‐electrode dielectrophoresis (DEP), which yielded 80% of the sensor devices featuring between one and five CNTs, is developed. The mechanism of floating‐electrode DEP on full arrays and individual devices to understand its self‐limiting behavior is studied. The resistance distributions across the array of CNT devices with respect to different DEP parameters are characterized. The CNT devices are then operated as liquid‐gated CNT field‐effect‐transistors (LG‐CNTFET) in liquid environment. Current dependency to the gate voltage of up to two orders of magnitude is recorded. Finally, the sensors are validated by studying the pH dependency of the LG‐CNTFET conductance and it is demonstrated that 73% of the CNT sensors of a given microsystem show a resistance decrease upon increasing the pH value. Close https://onlinelibrary.wiley.com/doi/abs/10.1002/adma.201606852 doi:10.1002/adma.201606852 Close
	Yada, Yuichiro; Mita, Takeshi; Sanada, Akihiro; Yano, Ryuichi; Kanzaki, Ryohei; Bakkum, Douglas J; Hierlemann, Andreas; Takahashi, Hirokazu Development of neural population activity toward self-organized criticality Journal Article Neuroscience, 343 , pp. 55-65, 2017, ISSN: 0306-4522. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks @article{Takahashi2017, title = {Development of neural population activity toward self-organized criticality}, author = {Yuichiro Yada and Takeshi Mita and Akihiro Sanada and Ryuichi Yano and Ryohei Kanzaki and Douglas J Bakkum and Andreas Hierlemann and Hirokazu Takahashi}, url = {http://www.sciencedirect.com/science/article/pii/S0306452216306522}, doi = {10.1016/j.neuroscience.2016.11.031}, issn = {0306-4522}, year = {2017}, date = {2017-02-20}, journal = {Neuroscience}, volume = {343}, pages = {55-65}, abstract = {Self-organized criticality (SoC), a spontaneous dynamic state established and maintained in networks of moderate complexity, is a universal characteristic of neural systems. Such systems produce cascades of spontaneous activity that are typically characterized by power-law distributions and rich, stable spatiotemporal patterns (i.e., neuronal avalanches). Since the dynamics of the critical state confer advantages in information processing within neuronal networks, it is of great interest to determine how criticality emerges during development. One possible mechanism is developmental, and includes axonal elongation during synaptogenesis and subsequent synaptic pruning in combination with the maturation of GABAergic inhibition (i.e., the integration then fragmentation process). Because experimental evidence for this mechanism remains inconclusive, we studied the developmental variation of neuronal avalanches in dissociated cortical neurons using high-density complementary metal-oxide semiconductor (CMOS) microelectrode arrays (MEAs). The spontaneous activities of nine cultures were monitored using CMOS MEAs from 4 to 30 days in vitro (DIV) at single-cell spatial resolution. While cells were immature, cultures demonstrated random-like patterns of activity and an exponential avalanche size distribution; this distribution was followed by a bimodal distribution, and finally a power-law-like distribution. The bimodal distribution was associated with a large-scale avalanche with a homogeneous spatiotemporal pattern, while the subsequent power-law distribution was associated with diverse patterns. These results suggest that the SoC emerges through a two-step process: the integration process accompanying the characteristic large-scale avalanche and the fragmentation process associated with diverse middle-size avalanches.}, keywords = {ETH-CMOS-MEA, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close Self-organized criticality (SoC), a spontaneous dynamic state established and maintained in networks of moderate complexity, is a universal characteristic of neural systems. Such systems produce cascades of spontaneous activity that are typically characterized by power-law distributions and rich, stable spatiotemporal patterns (i.e., neuronal avalanches). Since the dynamics of the critical state confer advantages in information processing within neuronal networks, it is of great interest to determine how criticality emerges during development. One possible mechanism is developmental, and includes axonal elongation during synaptogenesis and subsequent synaptic pruning in combination with the maturation of GABAergic inhibition (i.e., the integration then fragmentation process). Because experimental evidence for this mechanism remains inconclusive, we studied the developmental variation of neuronal avalanches in dissociated cortical neurons using high-density complementary metal-oxide semiconductor (CMOS) microelectrode arrays (MEAs). The spontaneous activities of nine cultures were monitored using CMOS MEAs from 4 to 30 days in vitro (DIV) at single-cell spatial resolution. While cells were immature, cultures demonstrated random-like patterns of activity and an exponential avalanche size distribution; this distribution was followed by a bimodal distribution, and finally a power-law-like distribution. The bimodal distribution was associated with a large-scale avalanche with a homogeneous spatiotemporal pattern, while the subsequent power-law distribution was associated with diverse patterns. These results suggest that the SoC emerges through a two-step process: the integration process accompanying the characteristic large-scale avalanche and the fragmentation process associated with diverse middle-size avalanches. Close http://www.sciencedirect.com/science/article/pii/S0306452216306522 doi:10.1016/j.neuroscience.2016.11.031 Close
2016
	Gong, Wei; Sencar, Jure; Bakkum, Douglas J; Jäckel, David; Obien, Marie Engelene J; Radivojevic, Milos; Hierlemann, Andreas Multiple single-unit long-term tracking on organotypic hippocampal slices using high-density microelectrode arrays Journal Article Frontiers in Neuroscience, 10 , pp. 1-16, 2016, ISSN: 1662453X. Abstract \| Links \| BibTeX \| Tags: Brain Slice, ETH-CMOS-MEA @article{Gong2016, title = {Multiple single-unit long-term tracking on organotypic hippocampal slices using high-density microelectrode arrays}, author = {Wei Gong and Jure Sencar and Douglas J Bakkum and David Jäckel and Marie Engelene J Obien and Milos Radivojevic and Andreas Hierlemann}, url = {https://www.frontiersin.org/articles/10.3389/fnins.2016.00537/full}, doi = {10.3389/fnins.2016.00537}, issn = {1662453X}, year = {2016}, date = {2016-11-22}, journal = {Frontiers in Neuroscience}, volume = {10}, pages = {1-16}, abstract = {A novel system to cultivate and record from organotypic brain slices directly on high-density microelectrode arrays (HD-MEA) was developed. This system allows for continuous recording of electrical activity of specific individual neurons at high spatial resolution while monitoring at the same time, neuronal network activity. For the first time, the electrical activity patterns of single neurons and the corresponding neuronal network in an organotypic hippocampal slice culture were studied during several consecutive weeks at daily intervals. An unsupervised iterative spike-sorting algorithm, based on PCA and k-means clustering, was developed to assign the activities to the single units. Spike-triggered average extracellular waveforms of an action potential recorded across neighboring electrodes, termed ‘footprints' of single-units were generated and tracked over weeks. The developed system offers the potential to study chronic impacts of drugs or genetic modifications on individual neurons in slice preparations over extended times.}, keywords = {Brain Slice, ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close A novel system to cultivate and record from organotypic brain slices directly on high-density microelectrode arrays (HD-MEA) was developed. This system allows for continuous recording of electrical activity of specific individual neurons at high spatial resolution while monitoring at the same time, neuronal network activity. For the first time, the electrical activity patterns of single neurons and the corresponding neuronal network in an organotypic hippocampal slice culture were studied during several consecutive weeks at daily intervals. An unsupervised iterative spike-sorting algorithm, based on PCA and k-means clustering, was developed to assign the activities to the single units. Spike-triggered average extracellular waveforms of an action potential recorded across neighboring electrodes, termed ‘footprints' of single-units were generated and tracked over weeks. The developed system offers the potential to study chronic impacts of drugs or genetic modifications on individual neurons in slice preparations over extended times. Close https://www.frontiersin.org/articles/10.3389/fnins.2016.00537/full doi:10.3389/fnins.2016.00537 Close
	Deligkaris, Kosmas; Bullmann, Torsten; Frey, Urs Extracellularly Recorded Somatic and Neuritic Signal Shapes and Classification Algorithms for High-Density Microelectrode Array Electrophysiology Journal Article Frontiers in Neuroscience, 10 , pp. 421, 2016, ISSN: 1662-453X. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks @article{Frey2016, title = {Extracellularly Recorded Somatic and Neuritic Signal Shapes and Classification Algorithms for High-Density Microelectrode Array Electrophysiology}, author = {Kosmas Deligkaris and Torsten Bullmann and Urs Frey}, url = {https://www.frontiersin.org/article/10.3389/fnins.2016.00421}, doi = {10.3389/fnins.2016.00421}, issn = {1662-453X}, year = {2016}, date = {2016-09-14}, journal = {Frontiers in Neuroscience}, volume = {10}, pages = {421}, abstract = {High-density microelectrode arrays (HDMEA) have been recently introduced to study principles of neural function at high spatial resolution. However, the exact nature of the experimentally observed extracellular action potentials (EAPs) is still incompletely understood. The soma, axon and dendrites of a neuron can all exhibit regenerative action potentials that could be sensed with HDMEA electrodes. Here, we investigate the contribution of distinct neuronal sources of activity in HDMEA recordings from low-density neuronal cultures. We recorded EAPs with HDMEAs having 11,011 electrodes and then fixed and immunostained the cultures with beta3-tubulin for high-resolution fluorescence imaging. Immunofluorescence images overlaid with the activity maps showed EAPs both at neuronal somata and distal neurites. Neuritic EAPs had mostly narrow triphasic shapes, consisting of a positive, a pronounced negative peak and a second positive peak. EAPs near somata had wide monophasic or biphasic shapes with a main negative peak, and following optional positive peak. We show that about 86% of EAP recordings consist of somatic spikes, while the remaining 14% represent neuritic spikes. Furthermore, the adaptation of the waveform shape during bursts of these neuritic spikes suggested that they originate from axons, rather than from dendrites. Our study improves the understanding of HDMEA signals and can aid in the identification of the source of EAPs.}, keywords = {ETH-CMOS-MEA, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close High-density microelectrode arrays (HDMEA) have been recently introduced to study principles of neural function at high spatial resolution. However, the exact nature of the experimentally observed extracellular action potentials (EAPs) is still incompletely understood. The soma, axon and dendrites of a neuron can all exhibit regenerative action potentials that could be sensed with HDMEA electrodes. Here, we investigate the contribution of distinct neuronal sources of activity in HDMEA recordings from low-density neuronal cultures. We recorded EAPs with HDMEAs having 11,011 electrodes and then fixed and immunostained the cultures with beta3-tubulin for high-resolution fluorescence imaging. Immunofluorescence images overlaid with the activity maps showed EAPs both at neuronal somata and distal neurites. Neuritic EAPs had mostly narrow triphasic shapes, consisting of a positive, a pronounced negative peak and a second positive peak. EAPs near somata had wide monophasic or biphasic shapes with a main negative peak, and following optional positive peak. We show that about 86% of EAP recordings consist of somatic spikes, while the remaining 14% represent neuritic spikes. Furthermore, the adaptation of the waveform shape during bursts of these neuritic spikes suggested that they originate from axons, rather than from dendrites. Our study improves the understanding of HDMEA signals and can aid in the identification of the source of EAPs. Close https://www.frontiersin.org/article/10.3389/fnins.2016.00421 doi:10.3389/fnins.2016.00421 Close
	Radivojevic, Milos; Jäckel, David; Altermatt, Michael; Müller, Jan; Viswam, Vijay; Hierlemann, Andreas; Bakkum, Douglas J Electrical Identification and Selective Microstimulation of Neuronal Compartments Based on Features of Extracellular Action Potentials Journal Article Scientific Reports, 6 (1), pp. 1-20, 2016, ISSN: 2045-2322. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks, Stimulation @article{Radivojevic2016, title = {Electrical Identification and Selective Microstimulation of Neuronal Compartments Based on Features of Extracellular Action Potentials}, author = {Milos Radivojevic and David Jäckel and Michael Altermatt and Jan Müller and Vijay Viswam and Andreas Hierlemann and Douglas J Bakkum}, url = {http://www.nature.com/articles/srep31332}, doi = {10.1038/srep31332}, issn = {2045-2322}, year = {2016}, date = {2016-08-11}, journal = {Scientific Reports}, volume = {6}, number = {1}, pages = {1-20}, abstract = {A detailed, high-spatiotemporal-resolution characterization of neuronal responses to local electrical fields and the capability of precise extracellular microstimulation of selected neurons are pivotal for studying and manipulating neuronal activity and circuits in networks and for developing neural prosthetics. Here, we studied cultured neocortical neurons by using high-density microelectrode arrays and optical imaging, complemented by the patch-clamp technique, and with the aim to correlate morphological and electrical features of neuronal compartments with their responsiveness to extracellular stimulation. We developed strategies to electrically identify any neuron in the network, while subcellular spatial resolution recording of extracellular action potential (AP) traces enabled their assignment to the axon initial segment (AIS), axonal arbor and proximal somatodendritic compartments. Stimulation at the AIS required low voltages and provided immediate, selective and reliable neuronal activation, whereas stimulation at the soma required high voltages and produced delayed and unreliable responses. Subthreshold stimulation at the soma depolarized the somatic membrane potential without eliciting APs.}, keywords = {ETH-CMOS-MEA, Neuronal Networks, Stimulation}, pubstate = {published}, tppubtype = {article} } Close A detailed, high-spatiotemporal-resolution characterization of neuronal responses to local electrical fields and the capability of precise extracellular microstimulation of selected neurons are pivotal for studying and manipulating neuronal activity and circuits in networks and for developing neural prosthetics. Here, we studied cultured neocortical neurons by using high-density microelectrode arrays and optical imaging, complemented by the patch-clamp technique, and with the aim to correlate morphological and electrical features of neuronal compartments with their responsiveness to extracellular stimulation. We developed strategies to electrically identify any neuron in the network, while subcellular spatial resolution recording of extracellular action potential (AP) traces enabled their assignment to the axon initial segment (AIS), axonal arbor and proximal somatodendritic compartments. Stimulation at the AIS required low voltages and provided immediate, selective and reliable neuronal activation, whereas stimulation at the soma required high voltages and produced delayed and unreliable responses. Subthreshold stimulation at the soma depolarized the somatic membrane potential without eliciting APs. Close http://www.nature.com/articles/srep31332 doi:10.1038/srep31332 Close
	Franke, Felix; Fiscella, Michele; Sevelev, Maksim; Roska, Botond; Hierlemann, Andreas; Azeredo da Silveira, Rava Structures of Neural Correlation and How They Favor Coding Journal Article Neuron, 89 (2), pp. 409-422, 2016, ISSN: 10974199. Abstract \| Links \| BibTeX \| Tags: Data Analysis, ETH-CMOS-MEA, Neuronal Networks, Retina @article{Franke2016, title = {Structures of Neural Correlation and How They Favor Coding}, author = {Felix Franke and Michele Fiscella and Maksim Sevelev and Botond Roska and Andreas Hierlemann and Rava {Azeredo da Silveira}}, url = {http://www.sciencedirect.com/science/article/pii/S0896627315011393?via%3Dihub}, doi = {10.1016/j.neuron.2015.12.037}, issn = {10974199}, year = {2016}, date = {2016-01-20}, journal = {Neuron}, volume = {89}, number = {2}, pages = {409-422}, publisher = {Elsevier Inc.}, abstract = {The neural representation of information suffers from "noise"-the trial-to-trial variability in the response of neurons. The impact of correlated noise upon population coding has been debated, but a direct connection between theory and experiment remains tenuous. Here, we substantiate this connection and propose a refined theoretical picture. Using simultaneous recordings from a population of direction-selective retinal ganglion cells, we demonstrate that coding benefits from noise correlations. The effect is appreciable already in small populations, yet it is a collective phenomenon. Furthermore, the stimulus-dependent structure of correlation is key. We develop simple functional models that capture the stimulus-dependent statistics. We then use them to quantify the performance of population coding, which depends upon interplays of feature sensitivities and noise correlations in the population. Because favorable structures of correlation emerge robustly in circuits with noisy, nonlinear elements, they will arise and benefit coding beyond the confines of retina. Coding in the brain suffers from the variability of neural responses. Using experiment and theory, Franke et al. show that this "noise" comes with a particular structure, which emerges from circuit properties and which counteracts the harmful effect of variability.}, keywords = {Data Analysis, ETH-CMOS-MEA, Neuronal Networks, Retina}, pubstate = {published}, tppubtype = {article} } Close The neural representation of information suffers from "noise"-the trial-to-trial variability in the response of neurons. The impact of correlated noise upon population coding has been debated, but a direct connection between theory and experiment remains tenuous. Here, we substantiate this connection and propose a refined theoretical picture. Using simultaneous recordings from a population of direction-selective retinal ganglion cells, we demonstrate that coding benefits from noise correlations. The effect is appreciable already in small populations, yet it is a collective phenomenon. Furthermore, the stimulus-dependent structure of correlation is key. We develop simple functional models that capture the stimulus-dependent statistics. We then use them to quantify the performance of population coding, which depends upon interplays of feature sensitivities and noise correlations in the population. Because favorable structures of correlation emerge robustly in circuits with noisy, nonlinear elements, they will arise and benefit coding beyond the confines of retina. Coding in the brain suffers from the variability of neural responses. Using experiment and theory, Franke et al. show that this "noise" comes with a particular structure, which emerges from circuit properties and which counteracts the harmful effect of variability. Close http://www.sciencedirect.com/science/article/pii/S0896627315011393?via%3Dihub doi:10.1016/j.neuron.2015.12.037 Close
	Yonehara, Keisuke; Fiscella, Michele; Drinnenberg, Antonia; Esposti, Federico; Trenholm, Stuart; Krol, Jacek; Franke, Felix; Scherf, Brigitte Gross; Kusnyerik, Akos; Müller, Jan; Szabo, Arnold; Jüttner, Josephine; Cordoba, Francisco; Reddy, Ashrithpal Police; Németh, János; Nagy, Zoltán Zsolt; Munier, Francis; Hierlemann, Andreas; Roska, Botond Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity Journal Article Neuron, 89 (1), pp. 177-193, 2016, ISSN: 10974199. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Retina @article{Yonehara2016, title = {Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity}, author = {Keisuke Yonehara and Michele Fiscella and Antonia Drinnenberg and Federico Esposti and Stuart Trenholm and Jacek Krol and Felix Franke and Brigitte Gross Scherf and Akos Kusnyerik and Jan Müller and Arnold Szabo and Josephine Jüttner and Francisco Cordoba and Ashrithpal Police Reddy and János Németh and Zoltán Zsolt Nagy and Francis Munier and Andreas Hierlemann and Botond Roska}, url = {http://www.sciencedirect.com/science/article/pii/S0896627315010387?via%3Dihub}, doi = {10.1016/j.neuron.2015.11.032}, issn = {10974199}, year = {2016}, date = {2016-01-06}, journal = {Neuron}, volume = {89}, number = {1}, pages = {177-193}, abstract = {Neuronal circuit asymmetries are important components of brain circuits, but the molecular pathways leading to their establishment remain unknown. Here we found that the mutation of FRMD7, a gene that is defective in human congenital nystagmus, leads to the selective loss of the horizontal optokinetic reflex in mice, as it does in humans. This is accompanied by the selective loss of horizontal direction selectivity in retinal ganglion cells and the transition from asymmetric to symmetric inhibitory input to horizontal direction-selective ganglion cells. In wild-type retinas, we found FRMD7 specifically expressed in starburst amacrine cells, the interneuron type that provides asymmetric inhibition to direction-selective retinal ganglion cells. This work identifies FRMD7 as a key regulator in establishing a neuronal circuit asymmetry, and it suggests the involvement of a specific inhibitory neuron type in the pathophysiology of a neurological disease.}, keywords = {ETH-CMOS-MEA, Retina}, pubstate = {published}, tppubtype = {article} } Close Neuronal circuit asymmetries are important components of brain circuits, but the molecular pathways leading to their establishment remain unknown. Here we found that the mutation of FRMD7, a gene that is defective in human congenital nystagmus, leads to the selective loss of the horizontal optokinetic reflex in mice, as it does in humans. This is accompanied by the selective loss of horizontal direction selectivity in retinal ganglion cells and the transition from asymmetric to symmetric inhibitory input to horizontal direction-selective ganglion cells. In wild-type retinas, we found FRMD7 specifically expressed in starburst amacrine cells, the interneuron type that provides asymmetric inhibition to direction-selective retinal ganglion cells. This work identifies FRMD7 as a key regulator in establishing a neuronal circuit asymmetry, and it suggests the involvement of a specific inhibitory neuron type in the pathophysiology of a neurological disease. Close http://www.sciencedirect.com/science/article/pii/S0896627315010387?via%3Dihub doi:10.1016/j.neuron.2015.11.032 Close
2015
	Jones, Ian L; Russell, Thomas L; Farrow, Karl; Fiscella, Michele; Franke, Felix; Müller, Jan; Jäckel, David; Hierlemann, Andreas A method for electrophysiological characterization of hamster retinal ganglion cells using a high-density CMOS microelectrode array Journal Article Frontiers in Neuroscience, 9 , pp. 360, 2015, ISSN: 1662453X. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Retina @article{Jones2015, title = {A method for electrophysiological characterization of hamster retinal ganglion cells using a high-density CMOS microelectrode array}, author = {Ian L Jones and Thomas L Russell and Karl Farrow and Michele Fiscella and Felix Franke and Jan Müller and David Jäckel and Andreas Hierlemann}, url = {https://www.frontiersin.org/articles/10.3389/fnins.2015.00360/full}, doi = {10.3389/fnins.2015.00360}, issn = {1662453X}, year = {2015}, date = {2015-10-13}, journal = {Frontiers in Neuroscience}, volume = {9}, pages = {360}, abstract = {Knowledge of neuronal cell types in the mammalian retina is important for the understanding of human retinal disease and the advancement of sight-restoring technology, such as retinal prosthetic devices. A somewhat less utilized animal model for retinal research is the hamster, which has a visual system that is characterized by an area centralis and a wide visual field with a broad binocular component. The hamster retina is optimally suited for recording on the microelectrode array (MEA), because it intrinsically lies flat on the MEA surface and yields robust, large-amplitude signals. However, information in the literature about hamster retinal ganglion cell functional types is scarce. The goal of our work is to develop a method featuring a high-density (HD) Complementary metal-oxide-semiconductor (CMOS) MEA technology along with a sequence of standardized visual stimuli in order to categorize ganglion cells in isolated Syrian Hamster (Mesocricetus auratus) retina. Since the HD-MEA is capable of recording at a higher spatial resolution than most MEA systems (17.5 um electrode pitch), we capitalized on this feature and were able to record from a large proportion of RGCs within a selected region. Secondly, we chose our stimuli so that they could be run during the experiment without intervention or computation steps. The visual stimulus set was designed to activate the receptive fields of most ganglion cells in parallel and to incorporate various visual features to which different cell types respond uniquely. Based on the ganglion cell responses, basic cell properties were determined: direction selectivity, speed tuning, width tuning, transience and latency. These properties were clustered in order to identify ganglion cell types in the hamster retina. Ultimately, we recorded up to a cell density 2780 cells/mm2 at 2 mm (42°) from the optic nerve head. Using 5 parameters extracted from the responses to visual stimuli, we obtained 7 ganglion cell types.}, keywords = {ETH-CMOS-MEA, Retina}, pubstate = {published}, tppubtype = {article} } Close Knowledge of neuronal cell types in the mammalian retina is important for the understanding of human retinal disease and the advancement of sight-restoring technology, such as retinal prosthetic devices. A somewhat less utilized animal model for retinal research is the hamster, which has a visual system that is characterized by an area centralis and a wide visual field with a broad binocular component. The hamster retina is optimally suited for recording on the microelectrode array (MEA), because it intrinsically lies flat on the MEA surface and yields robust, large-amplitude signals. However, information in the literature about hamster retinal ganglion cell functional types is scarce. The goal of our work is to develop a method featuring a high-density (HD) Complementary metal-oxide-semiconductor (CMOS) MEA technology along with a sequence of standardized visual stimuli in order to categorize ganglion cells in isolated Syrian Hamster (Mesocricetus auratus) retina. Since the HD-MEA is capable of recording at a higher spatial resolution than most MEA systems (17.5 um electrode pitch), we capitalized on this feature and were able to record from a large proportion of RGCs within a selected region. Secondly, we chose our stimuli so that they could be run during the experiment without intervention or computation steps. The visual stimulus set was designed to activate the receptive fields of most ganglion cells in parallel and to incorporate various visual features to which different cell types respond uniquely. Based on the ganglion cell responses, basic cell properties were determined: direction selectivity, speed tuning, width tuning, transience and latency. These properties were clustered in order to identify ganglion cell types in the hamster retina. Ultimately, we recorded up to a cell density 2780 cells/mm2 at 2 mm (42°) from the optic nerve head. Using 5 parameters extracted from the responses to visual stimuli, we obtained 7 ganglion cell types. Close https://www.frontiersin.org/articles/10.3389/fnins.2015.00360/full doi:10.3389/fnins.2015.00360 Close
	Fiscella, Michele; Franke, Felix; Farrow, Karl; Müller, Jan; Roska, Botond; Azeredo da Silveira, Rava ; Hierlemann, Andreas Visual coding with a population of direction-selective neurons Journal Article Journal of Neurophysiology, 114 (4), pp. 2485-2499, 2015, ISSN: 0022-3077. Abstract \| Links \| BibTeX \| Tags: Data Analysis, ETH-CMOS-MEA, Retina @article{Fiscella2015, title = {Visual coding with a population of direction-selective neurons}, author = {Michele Fiscella and Felix Franke and Karl Farrow and Jan Müller and Botond Roska and Rava {Azeredo da Silveira} and Andreas Hierlemann}, url = {http://jn.physiology.org/lookup/doi/10.1152/jn.00919.2014}, doi = {10.1152/jn.00919.2014}, issn = {0022-3077}, year = {2015}, date = {2015-08-19}, journal = {Journal of Neurophysiology}, volume = {114}, number = {4}, pages = {2485-2499}, abstract = {The brain decodes the visual scene from the action potentials of ∼20 retinal ganglion cell types. Among the retinal ganglion cells, direction-selective ganglion cells (DSGCs) encode motion direction. Several studies have focused on the encoding or decoding of motion direction by recording multiunit activity, mainly in the visual cortex. In this study, we simultaneously recorded from all four types of ON-OFF DSGCs of the rabbit retina using a microelectronics-based high-density microelectrode array (HDMEA) and decoded their concerted activity using probabilistic and linear decoders. Furthermore, we investigated how the modification of stimulus parameters (velocity, size, angle of moving object) and the use of different tuning curve fits influenced decoding precision. Finally, we simulated ON-OFF DSGC activity, based on real data, in order to understand how tuning curve widths and the angular distribution of the cells' preferred directions influence decoding performance. We found that probabilistic decoding strategies outperformed, on average, linear methods and that decoding precision was robust to changes in stimulus parameters such as velocity. The removal of noise correlations among cells, by random shuffling trials, caused a drop in decoding precision. Moreover, we found that tuning curves are broad in order to minimize large errors at the expense of a higher average error, and that the retinal direction-selective system would not substantially benefit, on average, from having more than four types of ON-OFF DSGCs or from a perfect alignment of the cells' preferred directions.}, keywords = {Data Analysis, ETH-CMOS-MEA, Retina}, pubstate = {published}, tppubtype = {article} } Close The brain decodes the visual scene from the action potentials of ∼20 retinal ganglion cell types. Among the retinal ganglion cells, direction-selective ganglion cells (DSGCs) encode motion direction. Several studies have focused on the encoding or decoding of motion direction by recording multiunit activity, mainly in the visual cortex. In this study, we simultaneously recorded from all four types of ON-OFF DSGCs of the rabbit retina using a microelectronics-based high-density microelectrode array (HDMEA) and decoded their concerted activity using probabilistic and linear decoders. Furthermore, we investigated how the modification of stimulus parameters (velocity, size, angle of moving object) and the use of different tuning curve fits influenced decoding precision. Finally, we simulated ON-OFF DSGC activity, based on real data, in order to understand how tuning curve widths and the angular distribution of the cells' preferred directions influence decoding performance. We found that probabilistic decoding strategies outperformed, on average, linear methods and that decoding precision was robust to changes in stimulus parameters such as velocity. The removal of noise correlations among cells, by random shuffling trials, caused a drop in decoding precision. Moreover, we found that tuning curves are broad in order to minimize large errors at the expense of a higher average error, and that the retinal direction-selective system would not substantially benefit, on average, from having more than four types of ON-OFF DSGCs or from a perfect alignment of the cells' preferred directions. Close http://jn.physiology.org/lookup/doi/10.1152/jn.00919.2014 doi:10.1152/jn.00919.2014 Close
	Okawa, Satoru; Mita, Takeshi; Bakkum, Douglas J; Frey, Urs; Hierlemann, Andreas; Kanzaki, Ryohei; Takahashi, Hirokazu Chronic Co-Variation of Neural Network Configuration and Activity in Mature Dissociated Cultures Journal Article Electronics and Communications in Japan, 98 (5), pp. 34-42, 2015, ISSN: 1942-9541. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks @article{Takahashi2015, title = {Chronic Co-Variation of Neural Network Configuration and Activity in Mature Dissociated Cultures}, author = {Satoru Okawa and Takeshi Mita and Douglas J Bakkum and Urs Frey and Andreas Hierlemann and Ryohei Kanzaki and Hirokazu Takahashi}, url = {http://onlinelibrary.wiley.com/doi/10.1002/ecj.11736/abstract;jsessionid=791557FA80CF36B1F78DC538C1618924.f03t02}, doi = {10.1002/ecj.11736}, issn = {1942-9541}, year = {2015}, date = {2015-04-08}, journal = {Electronics and Communications in Japan}, volume = {98}, number = {5}, pages = {34-42}, abstract = {Spatiotemporal neural patterns depend on the physical structure of neural circuits. Neural plasticity can thus be associated with changes in the circuit structure. For example, newborn neurons migrate toward existing, already matured, neural networks in order to participate in neural computation. In the present study, we have conducted two experiments to investigate how neural migration is associated with the development of neural activity in primary dissociated cultures of neuronal cells. In Experiment 1, using a mature culture, a high-density CMOS microelectrode array was used to continuously monitor neural migration and activity for more than two weeks. Consequently, we found that even in mature neuronal cultures neurons moved 2.0 ± 1.0 mum a day and that the moving distance was negatively correlated with their firing rate, suggesting that neurons featuring low firing rates tend to migrate actively. In Experiment 2 using a co-culture of mature and immature neurons, we found that immature neurons moved more actively than matured neurons to achieve functional connections to other neurons. These findings suggest that neurons with low firing rates as well as newborn neurons actively migrate in order to establish their connections and function in a neuronal network.}, keywords = {ETH-CMOS-MEA, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close Spatiotemporal neural patterns depend on the physical structure of neural circuits. Neural plasticity can thus be associated with changes in the circuit structure. For example, newborn neurons migrate toward existing, already matured, neural networks in order to participate in neural computation. In the present study, we have conducted two experiments to investigate how neural migration is associated with the development of neural activity in primary dissociated cultures of neuronal cells. In Experiment 1, using a mature culture, a high-density CMOS microelectrode array was used to continuously monitor neural migration and activity for more than two weeks. Consequently, we found that even in mature neuronal cultures neurons moved 2.0 ± 1.0 mum a day and that the moving distance was negatively correlated with their firing rate, suggesting that neurons featuring low firing rates tend to migrate actively. In Experiment 2 using a co-culture of mature and immature neurons, we found that immature neurons moved more actively than matured neurons to achieve functional connections to other neurons. These findings suggest that neurons with low firing rates as well as newborn neurons actively migrate in order to establish their connections and function in a neuronal network. Close http://onlinelibrary.wiley.com/doi/10.1002/ecj.11736/abstract;jsessionid=791557F[...] doi:10.1002/ecj.11736 Close
	Lewandowska, Marta K; Bakkum, Douglas J; Rompani, Santiago B; Hierlemann, Andreas Recording large extracellular spikes in microchannels along many axonal sites from individual neurons Journal Article PLoS ONE, 10 (3), pp. 1-24, 2015, ISSN: 19326203. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks @article{Lewandowska2015, title = {Recording large extracellular spikes in microchannels along many axonal sites from individual neurons}, author = {Marta K Lewandowska and Douglas J Bakkum and Santiago B Rompani and Andreas Hierlemann}, url = {http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118514}, doi = {10.1371/journal.pone.0118514}, issn = {19326203}, year = {2015}, date = {2015-03-03}, journal = {PLoS ONE}, volume = {10}, number = {3}, pages = {1-24}, abstract = {The numerous connections between neuronal cell bodies, made by their dendrites and axons, are vital for information processing in the brain. While dendrites and synapses have been extensively studied, axons have remained elusive to a large extent. We present a novel platform to study axonal physiology and information processing based on combining an 11,011-electrode high-density complementary metal-oxide semiconductor microelectrode array with a poly(dimethylsiloxane) channel device, which isolates axons from somas and, importantly, significantly amplifies recorded axonal signals. The combination of the microelectrode array with recording and stimulation capability with the microfluidic isolation channels permitted us to study axonal signal behavior at great detail. The device, featuring two culture chambers with over 30 channels spanning in between, enabled long-term recording of single spikes from isolated axons with signal amplitudes of 100 uV up to 2 mV. Propagating signals along axons could be recorded with 10 to 50 electrodes per channel. We (i) describe the performance and capabilities of our device for axonal electrophysiology, and (ii) present novel data on axonal signals facilitated by the device. Spontaneous action potentials with characteristic shapes propagated from somas along axons between the two compartments, and these unique shapes could be used to identify individual axons within channels that contained many axonal branches. Stimulation through the electrode array facilitated the identification of somas and their respective axons, enabling interfacing with different compartments of a single cell. Complex spike shapes observed in channels were traced back to single cells, and we show that more complicated spike shapes originate from a linear superposition of multiple axonal signals rather than signal distortion by the channels.}, keywords = {ETH-CMOS-MEA, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close The numerous connections between neuronal cell bodies, made by their dendrites and axons, are vital for information processing in the brain. While dendrites and synapses have been extensively studied, axons have remained elusive to a large extent. We present a novel platform to study axonal physiology and information processing based on combining an 11,011-electrode high-density complementary metal-oxide semiconductor microelectrode array with a poly(dimethylsiloxane) channel device, which isolates axons from somas and, importantly, significantly amplifies recorded axonal signals. The combination of the microelectrode array with recording and stimulation capability with the microfluidic isolation channels permitted us to study axonal signal behavior at great detail. The device, featuring two culture chambers with over 30 channels spanning in between, enabled long-term recording of single spikes from isolated axons with signal amplitudes of 100 uV up to 2 mV. Propagating signals along axons could be recorded with 10 to 50 electrodes per channel. We (i) describe the performance and capabilities of our device for axonal electrophysiology, and (ii) present novel data on axonal signals facilitated by the device. Spontaneous action potentials with characteristic shapes propagated from somas along axons between the two compartments, and these unique shapes could be used to identify individual axons within channels that contained many axonal branches. Stimulation through the electrode array facilitated the identification of somas and their respective axons, enabling interfacing with different compartments of a single cell. Complex spike shapes observed in channels were traced back to single cells, and we show that more complicated spike shapes originate from a linear superposition of multiple axonal signals rather than signal distortion by the channels. Close http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118514 doi:10.1371/journal.pone.0118514 Close
2014
	Bakkum, Douglas J; Radivojevic, Milos; Frey, Urs; Franke, Felix; Hierlemann, Andreas; Takahashi, Hirokazu Parameters for burst detection Journal Article Frontiers in Computational Neuroscience, 7 , pp. 1-12, 2014, ISSN: 1662-5188. Abstract \| Links \| BibTeX \| Tags: Data Analysis, ETH-CMOS-MEA @article{Bakkum2014, title = {Parameters for burst detection}, author = {Douglas J Bakkum and Milos Radivojevic and Urs Frey and Felix Franke and Andreas Hierlemann and Hirokazu Takahashi}, url = {http://journal.frontiersin.org/article/10.3389/fncom.2013.00193/abstract}, doi = {10.3389/fncom.2013.00193}, issn = {1662-5188}, year = {2014}, date = {2014-01-13}, journal = {Frontiers in Computational Neuroscience}, volume = {7}, pages = {1-12}, abstract = {Bursts of action potentials within neurons and throughout networks are believed to serve roles in how neurons handle and store information, both in vivo and in vitro. Accurate detection of burst occurrences and durations are therefore crucial for many studies. A number of algorithms have been proposed to do so, but a standard method has not been adopted. This is due, in part, to many algorithms requiring the adjustment of multiple ad-hoc parameters and further post-hoc criteria in order to produce satisfactory results. Here, we broadly catalog existing approaches and present a new approach requiring the selection of only a single parameter: the number of spikes N comprising the smallest burst to consider. A burst was identified if N spikes occurred in less than T ms, where the threshold T was automatically determined from observing a probability distribution of inter-spike-intervals. Performance was compared vs. different classes of detectors on data gathered from in vitro neuronal networks grown over microelectrode arrays. Our approach offered a number of useful features including: a simple implementation, no need for ad-hoc or post-hoc criteria, and precise assignment of burst boundary time points. Unlike existing approaches, detection was not biased toward larger bursts, allowing identification and analysis of a greater range of neuronal and network dynamics.}, keywords = {Data Analysis, ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close Bursts of action potentials within neurons and throughout networks are believed to serve roles in how neurons handle and store information, both in vivo and in vitro. Accurate detection of burst occurrences and durations are therefore crucial for many studies. A number of algorithms have been proposed to do so, but a standard method has not been adopted. This is due, in part, to many algorithms requiring the adjustment of multiple ad-hoc parameters and further post-hoc criteria in order to produce satisfactory results. Here, we broadly catalog existing approaches and present a new approach requiring the selection of only a single parameter: the number of spikes N comprising the smallest burst to consider. A burst was identified if N spikes occurred in less than T ms, where the threshold T was automatically determined from observing a probability distribution of inter-spike-intervals. Performance was compared vs. different classes of detectors on data gathered from in vitro neuronal networks grown over microelectrode arrays. Our approach offered a number of useful features including: a simple implementation, no need for ad-hoc or post-hoc criteria, and precise assignment of burst boundary time points. Unlike existing approaches, detection was not biased toward larger bursts, allowing identification and analysis of a greater range of neuronal and network dynamics. Close http://journal.frontiersin.org/article/10.3389/fncom.2013.00193/abstract doi:10.3389/fncom.2013.00193 Close
2013
	Bakkum, Douglas J; Frey, Urs; Radivojevic, Milos; Russell, Thomas L; Müller, Jan; Fiscella, Michele; Takahashi, Hirokazu; Hierlemann, Andreas Tracking axonal action potential propagation on a high-density microelectrode array across hundreds of sites Journal Article Nature Communications, 4 , pp. 1-12, 2013, ISSN: 2041-1723. Abstract \| Links \| BibTeX \| Tags: Data Analysis, ETH-CMOS-MEA, Neuronal Networks @article{Bakkum2013, title = {Tracking axonal action potential propagation on a high-density microelectrode array across hundreds of sites}, author = {Douglas J Bakkum and Urs Frey and Milos Radivojevic and Thomas L Russell and Jan Müller and Michele Fiscella and Hirokazu Takahashi and Andreas Hierlemann}, url = {http://www.nature.com/doifinder/10.1038/ncomms3181}, doi = {10.1038/ncomms3181}, issn = {2041-1723}, year = {2013}, date = {2013-07-19}, journal = {Nature Communications}, volume = {4}, pages = {1-12}, abstract = {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.}, keywords = {Data Analysis, ETH-CMOS-MEA, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close 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. Close http://www.nature.com/doifinder/10.1038/ncomms3181 doi:10.1038/ncomms3181 Close
	Müller, Jan; Bakkum, Douglas J; Hierlemann, Andreas Sub-millisecond closed-loop feedback stimulation between arbitrary sets of individual neurons. Journal Article Frontiers in Neural Circuits, 6 , pp. 121, 2013, ISSN: 1662-5110. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MEA Technology, Neuronal Networks, Stimulation @article{Muller2012, title = {Sub-millisecond closed-loop feedback stimulation between arbitrary sets of individual neurons.}, author = {Jan Müller and Douglas J Bakkum and Andreas Hierlemann}, url = {https://www.frontiersin.org/articles/10.3389/fncir.2012.00121/full}, doi = {10.3389/fncir.2012.00121}, issn = {1662-5110}, year = {2013}, date = {2013-01-10}, journal = {Frontiers in Neural Circuits}, volume = {6}, pages = {121}, abstract = {We present a system to artificially correlate the spike timing between sets of arbitrary neurons that were interfaced to a complementary metal-oxide-semiconductor (CMOS) high-density microelectrode array (MEA). The system features a novel reprogrammable and flexible event engine unit to detect arbitrary spatio-temporal patterns of recorded action potentials and is capable of delivering sub-millisecond closed-loop feedback of electrical stimulation upon trigger events in real-time. The relative timing between action potentials of individual neurons as well as the temporal pattern among multiple neurons, or neuronal assemblies, is considered an important factor governing memory and learning in the brain. Artificially changing timings between arbitrary sets of spiking neurons with our system could provide a "knob" to tune information processing in the network.}, keywords = {ETH-CMOS-MEA, MEA Technology, Neuronal Networks, Stimulation}, pubstate = {published}, tppubtype = {article} } Close We present a system to artificially correlate the spike timing between sets of arbitrary neurons that were interfaced to a complementary metal-oxide-semiconductor (CMOS) high-density microelectrode array (MEA). The system features a novel reprogrammable and flexible event engine unit to detect arbitrary spatio-temporal patterns of recorded action potentials and is capable of delivering sub-millisecond closed-loop feedback of electrical stimulation upon trigger events in real-time. The relative timing between action potentials of individual neurons as well as the temporal pattern among multiple neurons, or neuronal assemblies, is considered an important factor governing memory and learning in the brain. Artificially changing timings between arbitrary sets of spiking neurons with our system could provide a "knob" to tune information processing in the network. Close https://www.frontiersin.org/articles/10.3389/fncir.2012.00121/full doi:10.3389/fncir.2012.00121 Close
2012
	Fiscella, Michele; Farrow, Karl; Jones, Ian L; Jäckel, David; Müller, Jan; Frey, Urs; Bakkum, Douglas J; Hantz, Péter; Roska, Botond; Hierlemann, Andreas Recording from defined populations of retinal ganglion cells using a high-density CMOS-integrated microelectrode array with real-time switchable electrode selection Journal Article Journal of Neuroscience Methods, 211 (1), pp. 103-113, 2012, ISSN: 01650270. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Retina @article{Fiscella2012, title = {Recording from defined populations of retinal ganglion cells using a high-density CMOS-integrated microelectrode array with real-time switchable electrode selection}, author = {Michele Fiscella and Karl Farrow and Ian L Jones and David Jäckel and Jan Müller and Urs Frey and Douglas J Bakkum and Péter Hantz and Botond Roska and Andreas Hierlemann}, url = {http://www.sciencedirect.com/science/article/pii/S0165027012003287?via%3Dihub}, doi = {10.1016/j.jneumeth.2012.08.017}, issn = {01650270}, year = {2012}, date = {2012-08-16}, journal = {Journal of Neuroscience Methods}, volume = {211}, number = {1}, pages = {103-113}, publisher = {Elsevier B.V.}, abstract = {In order to understand how retinal circuits encode visual scenes, the neural activity of defined populations of retinal ganglion cells (RGCs) has to be investigated. Here we report on a method for stimulating, detecting, and subsequently targeting defined populations of RGCs. The possibility to select a distinct population of RGCs for extracellular recording enables the design of experiments that can increase our understanding of how these neurons extract precise spatio-temporal features from the visual scene, and how the brain interprets retinal signals. We used light stimulation to elicit a response from physiologically distinct types of RGCs and then utilized the dynamic-configurability capabilities of a microelectronics-based high-density microelectrode array (MEA) to record their synchronous action potentials. The layout characteristics of the MEA made it possible to stimulate and record from multiple, highly overlapping RGCs simultaneously without light-induced artifacts. The high-density of electrodes and the high signal-to-noise ratio of the MEA circuitry allowed for recording of the activity of each RGC on 14 ± 7 electrodes. The spatial features of the electrical activity of each RGC greatly facilitated spike sorting. We were thus able to localize, identify and record from defined RGCs within a region of mouse retina. In addition, we stimulated and recorded from genetically modified RGCs to demonstrate the applicability of optogenetic methods, which introduces an additional feature to target a defined cell type. The developed methodologies can likewise be applied to other neuronal preparations including brain slices or cultured neurons.}, keywords = {ETH-CMOS-MEA, Retina}, pubstate = {published}, tppubtype = {article} } Close In order to understand how retinal circuits encode visual scenes, the neural activity of defined populations of retinal ganglion cells (RGCs) has to be investigated. Here we report on a method for stimulating, detecting, and subsequently targeting defined populations of RGCs. The possibility to select a distinct population of RGCs for extracellular recording enables the design of experiments that can increase our understanding of how these neurons extract precise spatio-temporal features from the visual scene, and how the brain interprets retinal signals. We used light stimulation to elicit a response from physiologically distinct types of RGCs and then utilized the dynamic-configurability capabilities of a microelectronics-based high-density microelectrode array (MEA) to record their synchronous action potentials. The layout characteristics of the MEA made it possible to stimulate and record from multiple, highly overlapping RGCs simultaneously without light-induced artifacts. The high-density of electrodes and the high signal-to-noise ratio of the MEA circuitry allowed for recording of the activity of each RGC on 14 ± 7 electrodes. The spatial features of the electrical activity of each RGC greatly facilitated spike sorting. We were thus able to localize, identify and record from defined RGCs within a region of mouse retina. In addition, we stimulated and recorded from genetically modified RGCs to demonstrate the applicability of optogenetic methods, which introduces an additional feature to target a defined cell type. The developed methodologies can likewise be applied to other neuronal preparations including brain slices or cultured neurons. Close http://www.sciencedirect.com/science/article/pii/S0165027012003287?via%3Dihub doi:10.1016/j.jneumeth.2012.08.017 Close
	Jäckel, David; Frey, Urs; Fiscella, Michele; Franke, Felix; Hierlemann, Andreas Applicability of independent component analysis on high-density microelectrode array recordings Journal Article Journal of Neurophysiology, 108 (1), pp. 334-348, 2012, ISSN: 0022-3077. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Spike Sorting @article{Jackel2012, title = {Applicability of independent component analysis on high-density microelectrode array recordings}, author = {David Jäckel and Urs Frey and Michele Fiscella and Felix Franke and Andreas Hierlemann}, url = {http://jn.physiology.org/cgi/doi/10.1152/jn.01106.2011}, doi = {10.1152/jn.01106.2011}, issn = {0022-3077}, year = {2012}, date = {2012-04-04}, journal = {Journal of Neurophysiology}, volume = {108}, number = {1}, pages = {334-348}, abstract = {Emerging complementary metal oxide semiconductor (CMOS)-based, high-density microelectrode array (HD-MEA) devices provide high spatial resolution at subcellular level and a large number of readout channels. These devices allow for simultaneous recording of extracellular activity of a large number of neurons with every neuron being detected by multiple electrodes. To analyze the recorded signals, spiking events have to be assigned to individual neurons, a process referred to as "spike sorting." For a set of observed signals, which constitute a linear mixture of a set of source signals, independent component (IC) analysis (ICA) can be used to demix blindly the data and extract the individual source signals. This technique offers great potential to alleviate the problem of spike sorting in HD-MEA recordings, as it represents an unsupervised method to separate the neuronal sources. The separated sources or ICs then constitute estimates of single-neuron signals, and threshold detection on the ICs yields the sorted spike times. However, it is unknown to what extent extracellular neuronal recordings meet the requirements of ICA. In this paper, we evaluate the applicability of ICA to spike sorting of HD-MEA recordings. The analysis of extracellular neuronal signals, recorded at high spatiotemporal resolution, reveals that the recorded data cannot be modeled as a purely linear mixture. As a consequence, ICA fails to separate completely the neuronal signals and cannot be used as a stand-alone method for spike sorting in HD-MEA recordings. We assessed the demixing performance of ICA using simulated data sets and found that the performance strongly depends on neuronal density and spike amplitude. Furthermore, we show how postprocessing techniques can be used to overcome the most severe limitations of ICA. In combination with these postprocessing techniques, ICA represents a viable method to facilitate rapid spike sorting of multidimensional neuronal recordings.}, keywords = {ETH-CMOS-MEA, Spike Sorting}, pubstate = {published}, tppubtype = {article} } Close Emerging complementary metal oxide semiconductor (CMOS)-based, high-density microelectrode array (HD-MEA) devices provide high spatial resolution at subcellular level and a large number of readout channels. These devices allow for simultaneous recording of extracellular activity of a large number of neurons with every neuron being detected by multiple electrodes. To analyze the recorded signals, spiking events have to be assigned to individual neurons, a process referred to as "spike sorting." For a set of observed signals, which constitute a linear mixture of a set of source signals, independent component (IC) analysis (ICA) can be used to demix blindly the data and extract the individual source signals. This technique offers great potential to alleviate the problem of spike sorting in HD-MEA recordings, as it represents an unsupervised method to separate the neuronal sources. The separated sources or ICs then constitute estimates of single-neuron signals, and threshold detection on the ICs yields the sorted spike times. However, it is unknown to what extent extracellular neuronal recordings meet the requirements of ICA. In this paper, we evaluate the applicability of ICA to spike sorting of HD-MEA recordings. The analysis of extracellular neuronal signals, recorded at high spatiotemporal resolution, reveals that the recorded data cannot be modeled as a purely linear mixture. As a consequence, ICA fails to separate completely the neuronal signals and cannot be used as a stand-alone method for spike sorting in HD-MEA recordings. We assessed the demixing performance of ICA using simulated data sets and found that the performance strongly depends on neuronal density and spike amplitude. Furthermore, we show how postprocessing techniques can be used to overcome the most severe limitations of ICA. In combination with these postprocessing techniques, ICA represents a viable method to facilitate rapid spike sorting of multidimensional neuronal recordings. Close http://jn.physiology.org/cgi/doi/10.1152/jn.01106.2011 doi:10.1152/jn.01106.2011 Close
2011
	Hierlemann, Andreas; Frey, Urs; Hafizovic, Sadik; Heer, Flavio Growing cells atop microelectronic chips: Interfacing electrogenic cells in vitro with CMOS-based microelectrode arrays Journal Article Proceedings of the IEEE, 99 (2), pp. 252-284, 2011, ISSN: 00189219. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MEA Technology, Review @article{Hierlemann2011, title = {Growing cells atop microelectronic chips: Interfacing electrogenic cells in vitro with CMOS-based microelectrode arrays}, author = {Andreas Hierlemann and Urs Frey and Sadik Hafizovic and Flavio Heer}, url = {http://ieeexplore.ieee.org/document/5594982/}, doi = {10.1109/JPROC.2010.2066532}, issn = {00189219}, year = {2011}, date = {2011-02-01}, journal = {Proceedings of the IEEE}, volume = {99}, number = {2}, pages = {252-284}, abstract = {Complementary semiconductor-metal-oxide (CMOS) technology is a very powerful technology that can be more or less directly interfaced to electrogenic cells, like heart or brain cells in vitro. To this end, the cells are cultured directly atop the CMOS chips, which usually undergo dedicated postprocessing to obtain a reliable bidirectional interface via noble-metal microelectrodes or high-k dielectrics. The big advantages of using CMOS integrated circuits (ICs) include connectivity, the possibility to address a large number of microelectrodes on a tiny chip, and signal quality, the possibility to condition small signals right at the spot of their generation. CMOS will be demonstrated to constitute an enabling technology that opens a route to high-spatio-temporal-resolution and low-noise electrophysiological recordings from a variety of biological preparations, such as brain slices, or cultured cardiac and brain cells. The recording technique is extracellular and noninvasive, and the CMOS chips do not leak out any toxic compounds, so that the cells remain viable for extended times. In turn, the CMOS chips have been demonstrated to survive several months of culturing while being fully immersed in saline solution and being exposed to cellular metabolic products. The latter requires dedicated passivation and packaging techniques as will be shown. Fully integrated, monolithic microelectrode systems, which feature large numbers of tightly spaced microelectrodes and the associated circuitry units for bidirectional interaction (stimulation and recording), will be in the focus of this review. The respective dense microelectrode arrays (MEAs) with small pixels enable subcellular-resolution investigation of regions of interest in, e.g., neurobiological preparations, and, at the same time, the large number of electrodes allows for studying the activity of entire neuronal networks . Application areas include neuroscience, as the devices enable fundamental neurophysiological insights at the cellular and circuit level, as well as medical diagnostics and pharmacology.}, keywords = {ETH-CMOS-MEA, MEA Technology, Review}, pubstate = {published}, tppubtype = {article} } Close Complementary semiconductor-metal-oxide (CMOS) technology is a very powerful technology that can be more or less directly interfaced to electrogenic cells, like heart or brain cells in vitro. To this end, the cells are cultured directly atop the CMOS chips, which usually undergo dedicated postprocessing to obtain a reliable bidirectional interface via noble-metal microelectrodes or high-k dielectrics. The big advantages of using CMOS integrated circuits (ICs) include connectivity, the possibility to address a large number of microelectrodes on a tiny chip, and signal quality, the possibility to condition small signals right at the spot of their generation. CMOS will be demonstrated to constitute an enabling technology that opens a route to high-spatio-temporal-resolution and low-noise electrophysiological recordings from a variety of biological preparations, such as brain slices, or cultured cardiac and brain cells. The recording technique is extracellular and noninvasive, and the CMOS chips do not leak out any toxic compounds, so that the cells remain viable for extended times. In turn, the CMOS chips have been demonstrated to survive several months of culturing while being fully immersed in saline solution and being exposed to cellular metabolic products. The latter requires dedicated passivation and packaging techniques as will be shown. Fully integrated, monolithic microelectrode systems, which feature large numbers of tightly spaced microelectrodes and the associated circuitry units for bidirectional interaction (stimulation and recording), will be in the focus of this review. The respective dense microelectrode arrays (MEAs) with small pixels enable subcellular-resolution investigation of regions of interest in, e.g., neurobiological preparations, and, at the same time, the large number of electrodes allows for studying the activity of entire neuronal networks . Application areas include neuroscience, as the devices enable fundamental neurophysiological insights at the cellular and circuit level, as well as medical diagnostics and pharmacology. Close http://ieeexplore.ieee.org/document/5594982/ doi:10.1109/JPROC.2010.2066532 Close
2010
	Livi, Paolo; Heer, Flavio; Frey, Urs; Bakkum, Douglas J; Hierlemann, Andreas Compact voltage and current stimulation buffer for high-density microelectrode arrays Journal Article IEEE Transactions on Biomedical Circuits and Systems, 4 (6), pp. 372-378, 2010, ISSN: 19324545. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MEA Technology, Stimulation @article{Livi2010, title = {Compact voltage and current stimulation buffer for high-density microelectrode arrays}, author = {Paolo Livi and Flavio Heer and Urs Frey and Douglas J Bakkum and Andreas Hierlemann}, url = {http://ieeexplore.ieee.org/document/5617318/}, doi = {10.1109/TBCAS.2010.2080676}, issn = {19324545}, year = {2010}, date = {2010-11-01}, journal = {IEEE Transactions on Biomedical Circuits and Systems}, volume = {4}, number = {6}, pages = {372-378}, abstract = {We report on a compact (0.02 mm2 ) buffer for both voltage and current stimulation of electrogenic cells on a complementary metal-oxide semiconductor microelectrode array. In voltage mode, the circuit is a high-current class-AB voltage follower, based on a local common-mode feedback (LCMFB) amplifier. In current mode, the circuit is a current conveyor of type II, using the same LCMFB amplifier with cascode stages to increase the gain. The circuit shows good linearity in the 0.5-3.5 V input range and has extensively been used for stimulation of neuronal cultures.}, keywords = {ETH-CMOS-MEA, MEA Technology, Stimulation}, pubstate = {published}, tppubtype = {article} } Close We report on a compact (0.02 mm2 ) buffer for both voltage and current stimulation of electrogenic cells on a complementary metal-oxide semiconductor microelectrode array. In voltage mode, the circuit is a high-current class-AB voltage follower, based on a local common-mode feedback (LCMFB) amplifier. In current mode, the circuit is a current conveyor of type II, using the same LCMFB amplifier with cascode stages to increase the gain. The circuit shows good linearity in the 0.5-3.5 V input range and has extensively been used for stimulation of neuronal cultures. Close http://ieeexplore.ieee.org/document/5617318/ doi:10.1109/TBCAS.2010.2080676 Close
	Frey, Urs; Sedivy, Jan; Heer, Flavio; Pedron, Rene; Ballini, Marco; Müller, Jan; Bakkum, Douglas J; Hafizovic, Sadik; Faraci, Francesca D; Greve, Frauke; Kirstein, Kay Uwe; Hierlemann, Andreas Switch-matrix-based high-density microelectrode array in CMOS technology Journal Article IEEE Journal of Solid-State Circuits, 45 (2), pp. 467-482, 2010, ISSN: 00189200. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MEA Technology @article{Frey2010, title = {Switch-matrix-based high-density microelectrode array in CMOS technology}, author = {Urs Frey and Jan Sedivy and Flavio Heer and Rene Pedron and Marco Ballini and Jan Müller and Douglas J Bakkum and Sadik Hafizovic and Francesca D Faraci and Frauke Greve and Kay Uwe Kirstein and Andreas Hierlemann}, url = {http://ieeexplore.ieee.org/document/5405139/}, doi = {10.1109/JSSC.2009.2035196}, issn = {00189200}, year = {2010}, date = {2010-02-02}, journal = {IEEE Journal of Solid-State Circuits}, volume = {45}, number = {2}, pages = {467-482}, abstract = {We report on a CMOS-based microelectrode array (MEA) featuring 11, 011 metal electrodes and 126 channels, each of which comprises recording and stimulation electronics, for extracellular bidirectional communication with electrogenic cells, such as neurons or cardiomyocytes. The important features include: (i) high spatial resolution at (sub)cellular level with 3150 electrodes per mm2 (electrode diameter 7 um, electrode pitch 18 um); (ii) a reconflgurable routing of the recording sites to the 126 channels; and (iii) low noise levels.}, keywords = {ETH-CMOS-MEA, MEA Technology}, pubstate = {published}, tppubtype = {article} } Close We report on a CMOS-based microelectrode array (MEA) featuring 11, 011 metal electrodes and 126 channels, each of which comprises recording and stimulation electronics, for extracellular bidirectional communication with electrogenic cells, such as neurons or cardiomyocytes. The important features include: (i) high spatial resolution at (sub)cellular level with 3150 electrodes per mm2 (electrode diameter 7 um, electrode pitch 18 um); (ii) a reconflgurable routing of the recording sites to the 126 channels; and (iii) low noise levels. Close http://ieeexplore.ieee.org/document/5405139/ doi:10.1109/JSSC.2009.2035196 Close

61 entries « ‹ 1 of 2 › »

Selected Publications

High-resolution CMOS MEA platform to study neurons at subcellular, cellular, and network levels

Presenting measurements of neuronal preparations with a novel CMOS-based microelectrode array at high-spatiotemporal-resolution on subcellular, cellular, and network level.

J. Müller, M. Ballini, P. Livi, Y. Chen, M. Radivojevic, A. Shadmani, V. Viswam, I. L. Jones, M. Fiscella, R. Diggelmann, A. Stettler, U. Frey, D. J. Bakkum, and A. Hierlemann, “High-resolution CMOS MEA platform to study neurons at subcellular, cellular, and network levels,” Lab Chip, vol. 15, no. 13, pp. 2767–2780, May 2015.

Revealing Neuronal Function through Microelectrode Array Recordings

Reviewing the current understanding of microelectrode signals and the techniques for analyzing them, with focus on the ongoing advancements in microelectrode technology (in vivo and in vitro) and recent advanced microelectrode array measurement methods that facilitate the understanding of single neurons and network function.

M. E. J. Obien, K. Deligkaris, T. Bullmann, D. J. Bakkum, and U. Frey, “Revealing Neuronal Function through Microelectrode Array Recordings,” Front. Neurosci., 8:423, Jan 2015.

A 1024-Channel CMOS Microelectrode Array With 26,400 Electrodes for Recording and Stimulation of Electrogenic Cells In Vitro

A high-resolution CMOS-based microelectrode array featuring 1,024 low-noise readout channels, 26,400 electrodes at a density of 3,265 electrodes per mm², including on-chip 10bit ADCs and consuming only 75 mW.

M. Ballini, J. Muller, P. Livi, Y. Chen, U. Frey, A. Stettler, A. Shadmani, V. Viswam, I. L. Jones, D. Jackel, M. Radivojevic, M. K. Lewandowska, W. Gong, M. Fiscella, D. J. Bakkum, F. Heer, and A. Hierlemann, “A 1024-Channel CMOS Microelectrode Array With 26,400 Electrodes for Recording and Stimulation of Electrogenic Cells In Vitro,” IEEE Journal of Solid-State Circuits, vol. 49, no. 11, pp. 2705-2719, 2014.

Tracking axonal action potential propagation on a high-density microelectrode array across hundreds of sites

Demonstrating a method to electrically visualize action potential propagation on axons and revealing
large variations in velocity.

D. J. Bakkum, U. Frey, M. Radivojevic, T. L. Russell, J. Muller, M. Fiscella, H. Takahashi, and A. Hierlemann, “Tracking axonal action potential propagation on a high-density microelectrode array across hundreds of sites,” Nature Communications, 4:2181, Jul 2013.

Microelectronic System for High-Resolution Mapping of Extracellular Electric Fields Applied to Brain Slices

Recording and modeling extracellular action potentials of Purkinje cells at subcellular resolution.

U. Frey, U. Egert, F. Heer, S. Hafizovic, and A. Hierlemann, “Microelectronic System for High-Resolution Mapping of Extracellular Electric Fields Applied to Brain Slices,” Biosensors and Bioelectronics, vol. 24, no. 7, pp. 2191-2198, 2009.

Modulation of Cardiomyocyte Electrical Properties Using Regulated Bone Morphogenetic Protein-2 Expression

Controlling BMP-2 expression to modulate the electrophysiological properties of cardiomyocytes using an HD-MEA for detailed monitoring.

C. D. Sanchez-Bustamante, U. Frey, J. M. Kelm, A. Hierlemann, and M. Fussenegger,
“Modulation of Cardiomyocyte Electrical Properties Using Regulated Bone Morphogenetic Protein-2 Expression,” Tissue Engineering Part A, vol. 14, no. 12, pp. 1969-1988, 2008.

2022
	Xue, Xiaohan ; Buccino, Alessio Paolo ; Kumar, Sreedhar Saseendran ; Hierlemann, Andreas ; Bartram, Julian Inferring monosynaptic connections from paired dendritic spine Ca2+ imaging and large-scale recording of extracellular spiking Journal Article bioRxiv, 2022. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks @article{Xue2022, title = {Inferring monosynaptic connections from paired dendritic spine Ca2+ imaging and large-scale recording of extracellular spiking}, author = {Xue, Xiaohan and Buccino, Alessio Paolo and Kumar, Sreedhar Saseendran and Hierlemann, Andreas and Bartram, Julian}, doi = {10.1101/2022.02.16.480643}, year = {2022}, date = {2022-02-16}, journal = {bioRxiv}, abstract = {Techniques to identify monosynaptic connections between neurons have been vital for neuroscience research, facilitating important advancements concerning network topology, synaptic plasticity, and synaptic integration, among others. Here, we introduce a novel approach to identify and monitor monosynaptic connections using high-resolution dendritic spine Ca2+ imaging combined with simultaneous large-scale recording of extracellular electrical activity by means of high-density microelectrode arrays (HD-MEAs). We introduce an easily adoptable analysis pipeline that associates the imaged spine with its presynaptic unit and test it on in vitro recordings. The method is further validated and optimized by simulating synaptically-evoked spine Ca2+ transients based on measured spike trains in order to obtain simulated ground-truth connections. The proposed approach offers unique advantages as i) it can be used to identify monosynaptic connections with an accurate localization of the synapse within the dendritic tree, ii) it provides precise information of presynaptic spiking, and iii) postsynaptic spine Ca2+ signals and, finally, iv) the non-invasive nature of the proposed method allows for long-term measurements. The analysis toolkit together with the rich data sets that were acquired are made publicly available for further exploration by the research community.}, keywords = {ETH-CMOS-MEA, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close Techniques to identify monosynaptic connections between neurons have been vital for neuroscience research, facilitating important advancements concerning network topology, synaptic plasticity, and synaptic integration, among others. Here, we introduce a novel approach to identify and monitor monosynaptic connections using high-resolution dendritic spine Ca2+ imaging combined with simultaneous large-scale recording of extracellular electrical activity by means of high-density microelectrode arrays (HD-MEAs). We introduce an easily adoptable analysis pipeline that associates the imaged spine with its presynaptic unit and test it on in vitro recordings. The method is further validated and optimized by simulating synaptically-evoked spine Ca2+ transients based on measured spike trains in order to obtain simulated ground-truth connections. The proposed approach offers unique advantages as i) it can be used to identify monosynaptic connections with an accurate localization of the synapse within the dendritic tree, ii) it provides precise information of presynaptic spiking, and iii) postsynaptic spine Ca2+ signals and, finally, iv) the non-invasive nature of the proposed method allows for long-term measurements. The analysis toolkit together with the rich data sets that were acquired are made publicly available for further exploration by the research community. Close doi:10.1101/2022.02.16.480643 Close
2021
	Kagan, Brett J; Kitchen, Andy C; Tran, Nhi T; Parker, Bradyn J; Bhat, Anjali; Rollo, Ben; Razi, Adeel; Friston, Karl J In vitro neurons learn and exhibit sentience when embodied in a simulated game-world Journal Article BioRxiv, 2021. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, In-Vitro, MaxOne @article{Kagan2021, title = {In vitro neurons learn and exhibit sentience when embodied in a simulated game-world}, author = {Brett J. Kagan and Andy C. Kitchen and Nhi T. Tran and Bradyn J. Parker and Anjali Bhat and Ben Rollo and Adeel Razi and Karl J. Friston}, url = {https://www.biorxiv.org/content/10.1101/2021.12.02.471005v1 }, doi = {10.1101/2021.12.02.471005}, year = {2021}, date = {2021-12-03}, journal = {BioRxiv}, abstract = {Human brain organoids replicate much of the cellular diversity and developmental anatomy of the human brain. However, the physiological behavior of neuronal circuits within organoids remains relatively under-explored. With high-density CMOS microelectrode arrays (26,400 electrodes) and shank electrodes (960 electrodes), we probed broadband and three-dimensional extracellular field recordings generated by spontaneous activity of human brain organoids. These recordings simultaneously captured local field potentials (LFPs) and single-unit activity extracted through spike sorting. From spiking activity, we estimated a directed functional connectivity graph of synchronous neural network activity, which showed a large number of weak functional connections enmeshed within a network skeleton of significantly fewer strong connections. Treatment of the organoid with a benzodiazepine induced a reproducible signature response that shortened the inter-burst intervals, increased the uniformity of the firing pattern within each burst and decreased the population of weakly connected edges. Simultaneously examining the spontaneous LFPs and their phase alignment to spiking showed that spike bursts were coherent with theta oscillations in the LFPs. Our results demonstrate that human brain organoids have self-organized neuronal assemblies of sufficient size, cellular orientation, and functional connectivity to co-activate and generate field potentials from their collective transmembrane currents that phase-lock to spiking activity. These results point to the potential of brain organoids for the study of neuropsychiatric diseases, drug mechanisms, and the effects of external stimuli upon neuronal networks.}, keywords = {ETH-CMOS-MEA, In-Vitro, MaxOne}, pubstate = {published}, tppubtype = {article} } Close Human brain organoids replicate much of the cellular diversity and developmental anatomy of the human brain. However, the physiological behavior of neuronal circuits within organoids remains relatively under-explored. With high-density CMOS microelectrode arrays (26,400 electrodes) and shank electrodes (960 electrodes), we probed broadband and three-dimensional extracellular field recordings generated by spontaneous activity of human brain organoids. These recordings simultaneously captured local field potentials (LFPs) and single-unit activity extracted through spike sorting. From spiking activity, we estimated a directed functional connectivity graph of synchronous neural network activity, which showed a large number of weak functional connections enmeshed within a network skeleton of significantly fewer strong connections. Treatment of the organoid with a benzodiazepine induced a reproducible signature response that shortened the inter-burst intervals, increased the uniformity of the firing pattern within each burst and decreased the population of weakly connected edges. Simultaneously examining the spontaneous LFPs and their phase alignment to spiking showed that spike bursts were coherent with theta oscillations in the LFPs. Our results demonstrate that human brain organoids have self-organized neuronal assemblies of sufficient size, cellular orientation, and functional connectivity to co-activate and generate field potentials from their collective transmembrane currents that phase-lock to spiking activity. These results point to the potential of brain organoids for the study of neuropsychiatric diseases, drug mechanisms, and the effects of external stimuli upon neuronal networks. Close https://www.biorxiv.org/content/10.1101/2021.12.02.471005v1 doi:10.1101/2021.12.02.471005 Close
	Sundberg, Maria; Pinson, Hannah; Smith, Richard S; Winden, Kellen D; Venugopal, Pooja; Tai, Derek J C; Gusella, James F; Talkowski, Michael E; Walsh, Christopher A; Tegmark, Max; Sahin, Mustafa 16p11.2 deletion is associated with hyperactivation of human iPSC-derived dopaminergic neuron networks and is rescued by RHOA inhibition in vitro Journal Article Nature Communications, 12 (2897 ), 2021. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, IPSC, MaxOne @article{Sundberg2021, title = {16p11.2 deletion is associated with hyperactivation of human iPSC-derived dopaminergic neuron networks and is rescued by RHOA inhibition in vitro}, author = {Maria Sundberg and Hannah Pinson and Richard S. Smith and Kellen D. Winden and Pooja Venugopal and Derek J. C. Tai and James F. Gusella and Michael E. Talkowski and Christopher A. Walsh and Max Tegmark and Mustafa Sahin }, url = {https://www.nature.com/articles/s41467-021-23113-z}, doi = {10.1038/s41467-021-23113-z}, year = {2021}, date = {2021-05-18}, journal = {Nature Communications}, volume = {12}, number = {2897 }, abstract = {Reciprocal copy number variations (CNVs) of 16p11.2 are associated with a wide spectrum of neuropsychiatric and neurodevelopmental disorders. Here, we use human induced pluripotent stem cells (iPSCs)-derived dopaminergic (DA) neurons carrying CNVs of 16p11.2 duplication (16pdup) and 16p11.2 deletion (16pdel), engineered using CRISPR-Cas9. We show that 16pdel iPSC-derived DA neurons have increased soma size and synaptic marker expression compared to isogenic control lines, while 16pdup iPSC-derived DA neurons show deficits in neuronal differentiation and reduced synaptic marker expression. The 16pdel iPSC-derived DA neurons have impaired neurophysiological properties. The 16pdel iPSC-derived DA neuronal networks are hyperactive and have increased bursting in culture compared to controls. We also show that the expression of RHOA is increased in the 16pdel iPSC-derived DA neurons and that treatment with a specific RHOA-inhibitor, Rhosin, rescues the network activity of the 16pdel iPSC-derived DA neurons. Our data suggest that 16p11.2 deletion-associated iPSC-derived DA neuron hyperactivation can be rescued by RHOA inhibition.}, keywords = {ETH-CMOS-MEA, IPSC, MaxOne}, pubstate = {published}, tppubtype = {article} } Close Reciprocal copy number variations (CNVs) of 16p11.2 are associated with a wide spectrum of neuropsychiatric and neurodevelopmental disorders. Here, we use human induced pluripotent stem cells (iPSCs)-derived dopaminergic (DA) neurons carrying CNVs of 16p11.2 duplication (16pdup) and 16p11.2 deletion (16pdel), engineered using CRISPR-Cas9. We show that 16pdel iPSC-derived DA neurons have increased soma size and synaptic marker expression compared to isogenic control lines, while 16pdup iPSC-derived DA neurons show deficits in neuronal differentiation and reduced synaptic marker expression. The 16pdel iPSC-derived DA neurons have impaired neurophysiological properties. The 16pdel iPSC-derived DA neuronal networks are hyperactive and have increased bursting in culture compared to controls. We also show that the expression of RHOA is increased in the 16pdel iPSC-derived DA neurons and that treatment with a specific RHOA-inhibitor, Rhosin, rescues the network activity of the 16pdel iPSC-derived DA neurons. Our data suggest that 16p11.2 deletion-associated iPSC-derived DA neuron hyperactivation can be rescued by RHOA inhibition. Close https://www.nature.com/articles/s41467-021-23113-z doi:10.1038/s41467-021-23113-z Close
	Yuan, Xinyue; Hierlemann, Andreas; Frey, Urs Extracellular Recording of Entire Neural Networks Using a Dual-Mode Microelectrode Array With 19,584 Electrodes and High SNR Journal Article IEEE, 2021. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MEA Technology @article{Yuan2021, title = {Extracellular Recording of Entire Neural Networks Using a Dual-Mode Microelectrode Array With 19,584 Electrodes and High SNR}, author = {Xinyue Yuan and Andreas Hierlemann and Urs Frey}, url = {https://ieeexplore.ieee.org/document/9385387}, doi = {10.1109/JSSC.2021.3066043}, year = {2021}, date = {2021-03-24}, journal = {IEEE}, abstract = {Electrophysiological research on neural networks and their activity focuses on the recording and analysis of large data sets that include information of thousands of neurons. CMOS microelectrode arrays (MEAs) feature thousands of electrodes at a spatial resolution on the scale of single cells and are, therefore, ideal tools to support neural-network research. Moreover, they offer high spatio-temporal resolution and signal-to-noise ratio (SNR) to capture all features and subcellular-resolution details of neuronal signaling. Here, we present a dual-mode (DM) MEA, which enables simultaneous: 1) full-frame readout from all electrodes and 2) high-SNR readout from an arbitrarily selectable subset of electrodes. The DM-MEA includes 19,584 electrodes, 19,584 full-frame recording channels with noise levels of 10.4 μVrms in the action potential (AP) frequency band (300 Hz-5 kHz), 246 low-noise recording channels with noise levels of 3.0 μVrms in the AP band and eight stimulation units. The capacity to simultaneously perform full-frame and high-SNR recordings endows the presented DM-MEA with great flexibility for various applications in neuroscience and pharmacology.}, keywords = {ETH-CMOS-MEA, MEA Technology}, pubstate = {published}, tppubtype = {article} } Close Electrophysiological research on neural networks and their activity focuses on the recording and analysis of large data sets that include information of thousands of neurons. CMOS microelectrode arrays (MEAs) feature thousands of electrodes at a spatial resolution on the scale of single cells and are, therefore, ideal tools to support neural-network research. Moreover, they offer high spatio-temporal resolution and signal-to-noise ratio (SNR) to capture all features and subcellular-resolution details of neuronal signaling. Here, we present a dual-mode (DM) MEA, which enables simultaneous: 1) full-frame readout from all electrodes and 2) high-SNR readout from an arbitrarily selectable subset of electrodes. The DM-MEA includes 19,584 electrodes, 19,584 full-frame recording channels with noise levels of 10.4 μVrms in the action potential (AP) frequency band (300 Hz-5 kHz), 246 low-noise recording channels with noise levels of 3.0 μVrms in the AP band and eight stimulation units. The capacity to simultaneously perform full-frame and high-SNR recordings endows the presented DM-MEA with great flexibility for various applications in neuroscience and pharmacology. Close https://ieeexplore.ieee.org/document/9385387 doi:10.1109/JSSC.2021.3066043 Close
	Ronchi, Silvia; Buccino, Alessio Paolo; Prack, Gustavo; Kumar, Sreedhar Saseendran; Schröter, Manuel; Fiscella, Michele; Hierlemann, Andreas Microelectrode Arrays: Electrophysiological Phenotype Characterization of Human iPSC-Derived Neuronal Cell Lines by Means of High-Density Microelectrode Arrays Journal Article Advanced Biology, 5 (3), 2021. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, IPSC @article{Ronchi2021, title = {Microelectrode Arrays: Electrophysiological Phenotype Characterization of Human iPSC-Derived Neuronal Cell Lines by Means of High-Density Microelectrode Arrays}, author = {Silvia Ronchi and Alessio Paolo Buccino and Gustavo Prack and Sreedhar Saseendran Kumar and Manuel Schröter and Michele Fiscella and Andreas Hierlemann}, url = {https://onlinelibrary.wiley.com/doi/10.1002/adbi.202000223}, doi = {10.1002/adbi.202000223}, year = {2021}, date = {2021-03-17}, journal = {Advanced Biology}, volume = {5}, number = {3}, abstract = {In article number 2000223, Silvia Ronchi, Michele Fiscella, and co-workers show neurons plated on a high-density microelectrode array. The small electrode size and the tight spacing between the 26 400 electrodes enable functional extracellular electrophysiological characterization of neurons across scales, from subcellular-resolution features, like axons and dendrites, through individual neuronal cells to entire networks.}, keywords = {ETH-CMOS-MEA, IPSC}, pubstate = {published}, tppubtype = {article} } Close In article number 2000223, Silvia Ronchi, Michele Fiscella, and co-workers show neurons plated on a high-density microelectrode array. The small electrode size and the tight spacing between the 26 400 electrodes enable functional extracellular electrophysiological characterization of neurons across scales, from subcellular-resolution features, like axons and dendrites, through individual neuronal cells to entire networks. Close https://onlinelibrary.wiley.com/doi/10.1002/adbi.202000223 doi:10.1002/adbi.202000223 Close
	Sharf, Tal; van der Molen, Tjitse; Guzman, Elmer; Glasauer, Stella M K; Luna, Gabriel; Cheng, Zhouwei; Audouard, Morgane; Ranasinghe, Kamalini G; Kudo, Kiwamu; Nagarajan, Srikantan S; Tovar, Kenneth R; Petzold, Linda R; Hansma, Paul K; Kosik, Kenneth S Intrinsic network activity in human brain organoids Journal Article BioRxiv, 2021. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks, Organoids @article{Sharf2021, title = {Intrinsic network activity in human brain organoids}, author = {Tal Sharf and Tjitse van der Molen and Elmer Guzman and Stella M.K. Glasauer and Gabriel Luna and Zhouwei Cheng and Morgane Audouard and Kamalini G. Ranasinghe and Kiwamu Kudo and Srikantan S. Nagarajan and Kenneth R. Tovar and Linda R. Petzold and Paul K. Hansma and Kenneth S. Kosik}, url = {https://www.biorxiv.org/content/10.1101/2021.01.28.428643v1}, doi = {10.1101/2021.01.28.428643}, year = {2021}, date = {2021-01-28}, journal = {BioRxiv}, abstract = {Human brain organoids replicate much of the cellular diversity and developmental anatomy of the human brain. However, the physiological behavior of neuronal circuits within organoids remains relatively under-explored. With high-density CMOS microelectrode arrays and shank electrodes, we probed broadband and three-dimensional spontaneous activity of human brain organoids. These recordings simultaneously captured local field potentials (LFPs) and single unit activity. From spiking activity, we estimated a directed functional connectivity graph of synchronous neural network activity which showed a large number of weak functional connections enmeshed within a network skeleton of significantly fewer strong connections. Increasing the intrinsic inhibitory tone with a benzodiazepine altered the functional network graph of the organoid by suppressing the network skeleton. Simultaneously examining the spontaneous LFPs and their phase alignment to spiking showed that spike bursts were coherent with theta oscillations in the LFPs. An ensemble of spikes phase-locked to theta frequency oscillations were strongly interconnected as a sub-network within the larger network in which they were embedded. Our results demonstrate that human brain organoids have self-organized neuronal assemblies of sufficient size, cellular orientation, and functional connectivity to co-activate and generate field potentials from their collective transmembrane currents that phase-lock to spiking activity. These results point to the potential of brain organoids for the study of neuropsychiatric diseases, drug mechanisms, and the effects of external stimuli upon neuronal networks.}, keywords = {ETH-CMOS-MEA, Neuronal Networks, Organoids}, pubstate = {published}, tppubtype = {article} } Close Human brain organoids replicate much of the cellular diversity and developmental anatomy of the human brain. However, the physiological behavior of neuronal circuits within organoids remains relatively under-explored. With high-density CMOS microelectrode arrays and shank electrodes, we probed broadband and three-dimensional spontaneous activity of human brain organoids. These recordings simultaneously captured local field potentials (LFPs) and single unit activity. From spiking activity, we estimated a directed functional connectivity graph of synchronous neural network activity which showed a large number of weak functional connections enmeshed within a network skeleton of significantly fewer strong connections. Increasing the intrinsic inhibitory tone with a benzodiazepine altered the functional network graph of the organoid by suppressing the network skeleton. Simultaneously examining the spontaneous LFPs and their phase alignment to spiking showed that spike bursts were coherent with theta oscillations in the LFPs. An ensemble of spikes phase-locked to theta frequency oscillations were strongly interconnected as a sub-network within the larger network in which they were embedded. Our results demonstrate that human brain organoids have self-organized neuronal assemblies of sufficient size, cellular orientation, and functional connectivity to co-activate and generate field potentials from their collective transmembrane currents that phase-lock to spiking activity. These results point to the potential of brain organoids for the study of neuropsychiatric diseases, drug mechanisms, and the effects of external stimuli upon neuronal networks. Close https://www.biorxiv.org/content/10.1101/2021.01.28.428643v1 doi:10.1101/2021.01.28.428643 Close
2020
	Yuan, Xinyue; Schröter, Manuel; Obien, Marie Engelene J; Fiscella, Michele; Gong, Wei; Kikuchi, Tetsuhiro; Odawara, Aoi; Noji, Shuhei; Suzuki, Ikuro; Takahashi, Jun; Hierlemann, Andreas; Frey, Urs Versatile live-cell activity analysis platform for characterization of neuronal dynamics at single-cell and network level Journal Article Nature Communications, 11 (4854), 2020. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MEA Technology @article{Yuan2020, title = {Versatile live-cell activity analysis platform for characterization of neuronal dynamics at single-cell and network level}, author = {Xinyue Yuan and Manuel Schröter and Marie Engelene J. Obien and Michele Fiscella and Wei Gong and Tetsuhiro Kikuchi and Aoi Odawara and Shuhei Noji and Ikuro Suzuki and Jun Takahashi and Andreas Hierlemann and Urs Frey}, url = {https://www.nature.com/articles/s41467-020-18620-4#citeas}, doi = {10.1038/s41467-020-18620-4}, year = {2020}, date = {2020-09-25}, journal = {Nature Communications}, volume = {11}, number = {4854}, abstract = {Chronic imaging of neuronal networks in vitro has provided fundamental insights into mechanisms underlying neuronal function. Current labeling and optical imaging methods, however, cannot be used for continuous and long-term recordings of the dynamics and evolution of neuronal networks, as fluorescent indicators can cause phototoxicity. Here, we introduce a versatile platform for label-free, comprehensive and detailed electrophysiological live-cell imaging of various neurogenic cells and tissues over extended time scales. We report on a dual-mode high-density microelectrode array, which can simultaneously record in (i) full-frame mode with 19,584 recording sites and (ii) high-signal-to-noise mode with 246 channels. We set out to demonstrate the capabilities of this platform with recordings from primary and iPSC-derived neuronal cultures and tissue preparations over several weeks, providing detailed morpho-electrical phenotypic parameters at subcellular, cellular and network level. Moreover, we develop reliable analysis tools, which drastically increase the throughput to infer axonal morphology and conduction speed.}, keywords = {ETH-CMOS-MEA, MEA Technology}, pubstate = {published}, tppubtype = {article} } Close Chronic imaging of neuronal networks in vitro has provided fundamental insights into mechanisms underlying neuronal function. Current labeling and optical imaging methods, however, cannot be used for continuous and long-term recordings of the dynamics and evolution of neuronal networks, as fluorescent indicators can cause phototoxicity. Here, we introduce a versatile platform for label-free, comprehensive and detailed electrophysiological live-cell imaging of various neurogenic cells and tissues over extended time scales. We report on a dual-mode high-density microelectrode array, which can simultaneously record in (i) full-frame mode with 19,584 recording sites and (ii) high-signal-to-noise mode with 246 channels. We set out to demonstrate the capabilities of this platform with recordings from primary and iPSC-derived neuronal cultures and tissue preparations over several weeks, providing detailed morpho-electrical phenotypic parameters at subcellular, cellular and network level. Moreover, we develop reliable analysis tools, which drastically increase the throughput to infer axonal morphology and conduction speed. Close https://www.nature.com/articles/s41467-020-18620-4#citeas doi:10.1038/s41467-020-18620-4 Close
	Cowan, Cameron S; Renner, Magdalena; Gennaro, Martina De; Gross-Scherf, Brigitte; Goldblum, David; Hou, Yanyan; Munz, Martin; Rodrigues, Tiago M; Krol, Jacek; Szikra, Tamas; Cuttat, Rachel; Waldt, Annick; Papasaikas, Panagiotis; Diggelmann, Roland; Patino-Alvarez, Claudia P; Galliker, Patricia; Spirig, Stefan E; Pavlinic, Dinko; Gerber-Hollbach, Nadine; Schuierer, Sven; Srdanovic, Aldin; Balogh, Marton; Panero, Riccardo; Kusnyerik, Akos; Szabo, Arnold; Stadler, Michael B; Orgül, Selim; Picelli, Simone; Hasler, Pascal W; Hierlemann, Andreas; Scholl, Hendrik P N; Roma, Guglielmo; Nigsch, Florian; Roska, Botond Cell Types of the Human Retina and Its Organoids at Single-Cell Resolution Journal Article CellPress, 182 , pp. 1623–1640, 2020. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Organoids @article{Cowan2020, title = {Cell Types of the Human Retina and Its Organoids at Single-Cell Resolution}, author = {Cameron S. Cowan and Magdalena Renner and Martina De Gennaro and Brigitte Gross-Scherf and David Goldblum and Yanyan Hou and Martin Munz and Tiago M. Rodrigues and Jacek Krol and Tamas Szikra and Rachel Cuttat and Annick Waldt and Panagiotis Papasaikas and Roland Diggelmann and Claudia P. Patino-Alvarez and Patricia Galliker and Stefan E. Spirig and Dinko Pavlinic and Nadine Gerber-Hollbach and Sven Schuierer and Aldin Srdanovic and Marton Balogh and Riccardo Panero and Akos Kusnyerik and Arnold Szabo and Michael B. Stadler and Selim Orgül and Simone Picelli and Pascal W. Hasler and Andreas Hierlemann and Hendrik P.N. Scholl and Guglielmo Roma and Florian Nigsch and Botond Roska}, url = {https://www.cell.com/cell/fulltext/S0092-8674(20)31004-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420310047%3Fshowall%3Dtrue}, doi = {10.1016/j.cell.2020.08.013}, year = {2020}, date = {2020-09-17}, journal = {CellPress}, volume = {182}, pages = { 1623–1640}, abstract = {Human organoids recapitulating the cell-type diversity and function of their target organ are valuable for basic and translational research. We developed light-sensitive human retinal organoids with multiple nuclear and synaptic layers and functional synapses. We sequenced the RNA of 285,441 single cells from these organoids at seven developmental time points and from the periphery, fovea, pigment epithelium and choroid of light-responsive adult human retinas, and performed histochemistry. Cell types in organoids matured in vitro to a stable “developed” state at a rate similar to human retina development in vivo. Transcriptomes of organoid cell types converged toward the transcriptomes of adult peripheral retinal cell types. Expression of disease-associated genes was cell-type-specific in adult retina, and cell-type specificity was retained in organoids. We implicate unexpected cell types in diseases such as macular degeneration. This resource identifies cellular targets for studying disease mechanisms in organoids and for targeted repair in human retinas.}, keywords = {ETH-CMOS-MEA, Organoids}, pubstate = {published}, tppubtype = {article} } Close Human organoids recapitulating the cell-type diversity and function of their target organ are valuable for basic and translational research. We developed light-sensitive human retinal organoids with multiple nuclear and synaptic layers and functional synapses. We sequenced the RNA of 285,441 single cells from these organoids at seven developmental time points and from the periphery, fovea, pigment epithelium and choroid of light-responsive adult human retinas, and performed histochemistry. Cell types in organoids matured in vitro to a stable “developed” state at a rate similar to human retina development in vivo. Transcriptomes of organoid cell types converged toward the transcriptomes of adult peripheral retinal cell types. Expression of disease-associated genes was cell-type-specific in adult retina, and cell-type specificity was retained in organoids. We implicate unexpected cell types in diseases such as macular degeneration. This resource identifies cellular targets for studying disease mechanisms in organoids and for targeted repair in human retinas. Close https://www.cell.com/cell/fulltext/S0092-8674(20)31004-7?_returnURL=https%3A%2F%[...] doi:10.1016/j.cell.2020.08.013 Close
	Ronchi, Silvia; Buccino, Alessio Paolo; Prack, Gustavo; Kumar, Sreedhar Saseendran; Schröter, Manuel; Fiscella, Michele; Hierlemann, Andreas Electrophysiological Phenotype Characterization of Human iPSC-Derived Neuronal Cell Lines by Means of High-Density Microelectrode Arrays Journal Article BioRxiv, 2020. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, IPSC @article{Ronchi2020, title = {Electrophysiological Phenotype Characterization of Human iPSC-Derived Neuronal Cell Lines by Means of High-Density Microelectrode Arrays}, author = {Silvia Ronchi and Alessio Paolo Buccino and Gustavo Prack and Sreedhar Saseendran Kumar and Manuel Schröter and Michele Fiscella and Andreas Hierlemann }, url = {https://www.biorxiv.org/content/10.1101/2020.09.02.271403v1}, doi = {10.1101/2020.09.02.271403}, year = {2020}, date = {2020-09-02}, journal = {BioRxiv}, abstract = {Recent advances in the field of cellular reprogramming have opened a route to study the fundamental mechanisms underlying common neurological disorders. High-density microelectrode-arrays (HD-MEAs) provide unprecedented means to study neuronal physiology at different scales, ranging from network through single-neuron to subcellular features. In this work, we used HD-MEAs in vitro to characterize and compare human induced-pluripotent-stem-cell (iPSC)-derived dopaminergic and motor neurons, including isogenic neuronal lines modeling Parkinson’s disease and amyotrophic lateral sclerosis. We established reproducible electrophysiological network, single-cell and subcellular metrics, which were used for phenotype characterization and drug testing. Metrics such as burst shapes and axonal velocity enabled the distinction of healthy and diseased neurons. The HD-MEA metrics could also be used to detect the effects of dosing the drug retigabine to human motor neurons. Finally, we showed that the ability to detect drug effects and the observed culture-to-culture variability critically depend on the number of available recording electrodes}, keywords = {ETH-CMOS-MEA, IPSC}, pubstate = {published}, tppubtype = {article} } Close Recent advances in the field of cellular reprogramming have opened a route to study the fundamental mechanisms underlying common neurological disorders. High-density microelectrode-arrays (HD-MEAs) provide unprecedented means to study neuronal physiology at different scales, ranging from network through single-neuron to subcellular features. In this work, we used HD-MEAs in vitro to characterize and compare human induced-pluripotent-stem-cell (iPSC)-derived dopaminergic and motor neurons, including isogenic neuronal lines modeling Parkinson’s disease and amyotrophic lateral sclerosis. We established reproducible electrophysiological network, single-cell and subcellular metrics, which were used for phenotype characterization and drug testing. Metrics such as burst shapes and axonal velocity enabled the distinction of healthy and diseased neurons. The HD-MEA metrics could also be used to detect the effects of dosing the drug retigabine to human motor neurons. Finally, we showed that the ability to detect drug effects and the observed culture-to-culture variability critically depend on the number of available recording electrodes Close https://www.biorxiv.org/content/10.1101/2020.09.02.271403v1 doi:10.1101/2020.09.02.271403 Close
	Idrees, Saad; Baumann, Matthias P; Franke, Felix; Münch, Thomas A; Hafed, Ziad M Perceptual saccadic suppression starts in the retina Journal Article Nature Communications, 11 (1977), 2020. Links \| BibTeX \| Tags: ETH-CMOS-MEA, MaxOne, Retina @article{Idrees2020, title = {Perceptual saccadic suppression starts in the retina}, author = {Saad Idrees and Matthias P. Baumann and Felix Franke and Thomas A. Münch and Ziad M. Hafed}, url = {https://www.nature.com/articles/s41467-020-15890-w}, doi = {10.1038/s41467-020-15890-w}, year = {2020}, date = {2020-04-24}, journal = {Nature Communications}, volume = {11}, number = {1977}, keywords = {ETH-CMOS-MEA, MaxOne, Retina}, pubstate = {published}, tppubtype = {article} } Close https://www.nature.com/articles/s41467-020-15890-w doi:10.1038/s41467-020-15890-w Close
	Obaid, Abdulmalik; Hanna, Mina-Elrahb; Wu, Yu-Wei; Kollo, Mihaly; Racz, Romeo; Angle, Matthew R; Muller, Jan; Brackbill, Nora; Wray, William; Franke, Felix; Chichilnski, E J; Hierlemann, Andreas; Ding, Jun B; Schaefer, Andreas T; Melosh, Nicholas A Massively parallel microwire arrays integrated withCMOS chips for neural recording Journal Article Science Advances, 2020. Abstract \| Links \| BibTeX \| Tags: Electrodes, ETH-CMOS-MEA @article{Obaid2020, title = {Massively parallel microwire arrays integrated withCMOS chips for neural recording}, author = {Abdulmalik Obaid and Mina-Elrahb Hanna and Yu-Wei Wu and Mihaly Kollo and Romeo Racz and Matthew R Angle and Jan Muller and Nora Brackbill and William Wray and Felix Franke and E J Chichilnski and Andreas Hierlemann and Jun B. Ding and Andreas T. Schaefer and Nicholas A. Melosh}, url = {https://advances.sciencemag.org/content/6/12/eaay2789}, doi = {10.1126/sciadv.aay2789}, year = {2020}, date = {2020-03-20}, journal = {Science Advances}, abstract = {Multi-channel electrical recordings of neural activity in the brain is an increasingly powerful method revealing new aspects of neural communication, computation, and prosthetics. However, while planar silicon-based CMOS devices in conventional electronics scale rapidly, neural interface devices have not kept pace. Here, we present a new strategy to interface silicon-based chips with three-dimensional microwire arrays, providing the link between rapidly-developing electronics and high density neural interfaces. The system consists of a bundle of microwires mated to large-scale microelectrode arrays, such as camera chips. This system has excellent recording performance, demonstrated via single unit and local-field potential recordings in isolated retina and in the motor cortex or striatum of awake moving mice. The modular design enables a variety of microwire types and sizes to be integrated with different types of pixel arrays, connecting the rapid progress of commercial multiplexing, digitisation and data acquisition hardware together with a three-dimensional neural interface.}, keywords = {Electrodes, ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close Multi-channel electrical recordings of neural activity in the brain is an increasingly powerful method revealing new aspects of neural communication, computation, and prosthetics. However, while planar silicon-based CMOS devices in conventional electronics scale rapidly, neural interface devices have not kept pace. Here, we present a new strategy to interface silicon-based chips with three-dimensional microwire arrays, providing the link between rapidly-developing electronics and high density neural interfaces. The system consists of a bundle of microwires mated to large-scale microelectrode arrays, such as camera chips. This system has excellent recording performance, demonstrated via single unit and local-field potential recordings in isolated retina and in the motor cortex or striatum of awake moving mice. The modular design enables a variety of microwire types and sizes to be integrated with different types of pixel arrays, connecting the rapid progress of commercial multiplexing, digitisation and data acquisition hardware together with a three-dimensional neural interface. Close https://advances.sciencemag.org/content/6/12/eaay2789 doi:10.1126/sciadv.aay2789 Close
2019
	Ronchi, Silvia; Fiscella, Michele; Marchetti, Camilla; Viswam, Vijay; Muller, Jan; Frey, Urs; Hierlemann, Andreas Single-Cell Electrical Stimulation Using CMOS-Based High-Density Microelectrode Arrays Journal Article Frontiers in Neuroscience, 13 , 2019, ISSN: 1662-453X . Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Stimulation @article{Ronchi2019, title = {Single-Cell Electrical Stimulation Using CMOS-Based High-Density Microelectrode Arrays}, author = {Silvia Ronchi and Michele Fiscella and Camilla Marchetti and Vijay Viswam and Jan Muller and Urs Frey and Andreas Hierlemann}, url = {https://www.frontiersin.org/article/10.3389/fnins.2019.00208 }, doi = {10.3389/fnins.2019.00208 }, issn = {1662-453X }, year = {2019}, date = {2019-03-13}, journal = {Frontiers in Neuroscience}, volume = {13}, abstract = {Non-invasive electrical stimulation can be used to study and control neural activity in the brain or to alleviate somatosensory dysfunctions. One intriguing prospect is to precisely stimulate individual targeted neurons. Here, we investigated single-neuron current and voltage stimulation in vitro using high-density microelectrode arrays featuring 26’400 bidirectional electrodes at a pitch of 17.5 µm and an electrode area of 5 × 9 µm². We determined optimal waveforms, amplitudes and durations for both stimulation modes. Owing to the high spatial resolution of our arrays and the close proximity of the electrodes to the respective neurons, we were able to stimulate the axon initial segments (AIS) with charges of less than 2 picoCoulombs. This resulted in minimal artifact production and reliable readout of stimulation efficiency directly at the soma of the stimulated cell. Stimulation signals as low as 70 mV or 100 nA,with pulse durations as short as 18 µs, yielded measurable action potential initiation and propagation. We found that the required stimulation signal amplitudes decreased with cell growth and development and that stimulation efficiency did not improve at higher electric fields generated by simultaneous multi-electrode stimulation.}, keywords = {ETH-CMOS-MEA, Stimulation}, pubstate = {published}, tppubtype = {article} } Close Non-invasive electrical stimulation can be used to study and control neural activity in the brain or to alleviate somatosensory dysfunctions. One intriguing prospect is to precisely stimulate individual targeted neurons. Here, we investigated single-neuron current and voltage stimulation in vitro using high-density microelectrode arrays featuring 26’400 bidirectional electrodes at a pitch of 17.5 µm and an electrode area of 5 × 9 µm². We determined optimal waveforms, amplitudes and durations for both stimulation modes. Owing to the high spatial resolution of our arrays and the close proximity of the electrodes to the respective neurons, we were able to stimulate the axon initial segments (AIS) with charges of less than 2 picoCoulombs. This resulted in minimal artifact production and reliable readout of stimulation efficiency directly at the soma of the stimulated cell. Stimulation signals as low as 70 mV or 100 nA,with pulse durations as short as 18 µs, yielded measurable action potential initiation and propagation. We found that the required stimulation signal amplitudes decreased with cell growth and development and that stimulation efficiency did not improve at higher electric fields generated by simultaneous multi-electrode stimulation. Close https://www.frontiersin.org/article/10.3389/fnins.2019.00208 doi:10.3389/fnins.2019.00208 Close
	Dudina, Alexandra; Seichepine, Florent; Chen, Yihui; and Stettler, Alexander; Hierlemann, Andreas; and Frey, Urs Monolithic CMOS sensor platform featuring an array of 9’216 carbon-nanotube-sensor elements and low-noise, wide-bandwidth and wide-dynamic-range readout circuitry Journal Article Sensors and Actuators B: Chemical, 279 , pp. 255-266, 2019. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @article{Dudina2019, title = {Monolithic CMOS sensor platform featuring an array of 9’216 carbon-nanotube-sensor elements and low-noise, wide-bandwidth and wide-dynamic-range readout circuitry}, author = {Alexandra Dudina and Florent Seichepine and Yihui Chen and and Alexander Stettler and Andreas Hierlemann and and Urs Frey}, url = {https://www.sciencedirect.com/science/article/pii/S0925400518317672?via%3Dihub}, doi = {10.1016/j.snb.2018.10.004}, year = {2019}, date = {2019-01-15}, journal = {Sensors and Actuators B: Chemical}, volume = {279}, pages = {255-266}, abstract = {We present the design and characterization of a monolithic complementary metal–oxide–semiconductor (CMOS) biosensor platform comprising of a switch-matrix-based array of 9′216 carbon nanotube field-effect transistors (CNTFETs) and associated readout circuitry. The switch-matrix allows for flexible selection and simultaneous routing of 96 sensor elements to the corresponding readout channels. A low-noise, wide-bandwidth, wide-dynamic-range transimpedance continuous-time amplifier architecture has been implemented to facilitate resistance measurements in the range between 50 kΩ and 1 GΩ at a bandwidth of up to 1 MHz. The achieved accuracy of the resistance measurements over the whole range is 4%. The system has been successfully fabricated and tested and shows a noise performance equal to 2.14 pArms at a bandwidth of 1 kHz and 0.84 nArms at a bandwidth of 1 MHz. A batch integration of the CNTFETs has been achieved by using a dielectrophoresis (DEP)–based manipulation technique. The current-voltage curves of CNTFETs have been acquired, and the sensing capabilities of the system have been demonstrated by recording resistance changes of CNTFETs upon exposure to solutions with different pH values and different concentrations of NaCl. The smallest resolvable concentrations for the respective analytes were estimated to amount to 0.025 pH-units and 4 mM NaCl.}, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close We present the design and characterization of a monolithic complementary metal–oxide–semiconductor (CMOS) biosensor platform comprising of a switch-matrix-based array of 9′216 carbon nanotube field-effect transistors (CNTFETs) and associated readout circuitry. The switch-matrix allows for flexible selection and simultaneous routing of 96 sensor elements to the corresponding readout channels. A low-noise, wide-bandwidth, wide-dynamic-range transimpedance continuous-time amplifier architecture has been implemented to facilitate resistance measurements in the range between 50 kΩ and 1 GΩ at a bandwidth of up to 1 MHz. The achieved accuracy of the resistance measurements over the whole range is 4%. The system has been successfully fabricated and tested and shows a noise performance equal to 2.14 pArms at a bandwidth of 1 kHz and 0.84 nArms at a bandwidth of 1 MHz. A batch integration of the CNTFETs has been achieved by using a dielectrophoresis (DEP)–based manipulation technique. The current-voltage curves of CNTFETs have been acquired, and the sensing capabilities of the system have been demonstrated by recording resistance changes of CNTFETs upon exposure to solutions with different pH values and different concentrations of NaCl. The smallest resolvable concentrations for the respective analytes were estimated to amount to 0.025 pH-units and 4 mM NaCl. Close https://www.sciencedirect.com/science/article/pii/S0925400518317672?via%3Dihub doi:10.1016/j.snb.2018.10.004 Close
	Shadmani, Amir; Viswam, Vijay; Chen, Yihui; Bounik, Raziyeh; Dragas, Jelena; Radivojevic, Milos; Geissler, Sydney; Sitnikov, Sergey; Muller, Jan; Hierlemann, Andreas Stimulation and Artifact-suppression Techniques for in-vitro High-density Microelectrode Array Systems. Journal Article IEEE Transactions on Biomedical Engineering, 2019. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @article{Shadmani2019b, title = {Stimulation and Artifact-suppression Techniques for in-vitro High-density Microelectrode Array Systems.}, author = {Amir Shadmani and Vijay Viswam and Yihui Chen and Raziyeh Bounik and Jelena Dragas and Milos Radivojevic and Sydney Geissler and Sergey Sitnikov and Jan Muller and Andreas Hierlemann }, url = {https://ieeexplore.ieee.org/document/8599003}, doi = {10.1109/TBME.2018.2890530}, year = {2019}, date = {2019-01-01}, journal = {IEEE Transactions on Biomedical Engineering}, abstract = {We present novel voltage stimulation buffers with controlled output current, along with recording circuits featuring adjustable high-pass cut-off filtering to perform efficient stimulation while actively suppressing stimulation artifacts in high-density microelectrode arrays. Owing to the dense packing and close proximity of the electrodes in such systems, a stimulation through one electrode can cause large electrical artifacts on neighboring electrodes that easily saturate the corresponding recording amplifiers. To suppress such artifacts, the high-pass corner frequencies of all available 2048 recording channels can be raised from several Hz to several kHz by applying a "soft-reset" or pole-shifting technique. With the implemented artifact suppression technique, the saturation time of the recording circuits, connected to electrodes in immediate vicinity to the stimulation site, could be reduced to less than 150μs. For the stimulation buffer, we developed a circuit, which can operate in two modes: either control of only the stimulation voltage, or control of current and voltage during stimulation. The voltage-only controlled mode employs a local common-mode feedback operational transconductance amplifier with a near rail-to-rail input/output range, suitable for driving high capacitive loads. The current/voltage controlled mode is based on a positive current conveyor generating adjustable output currents, while its upper and lower output voltages are limited by two feedback loops. The current/voltage controlled circuit can generate stimulation pulses up to 30 μA with less than ±0.1% linearity error in the low-current mode, and up to 300 μA with less than ±0.2% linearity error in the high-current mode.}, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close We present novel voltage stimulation buffers with controlled output current, along with recording circuits featuring adjustable high-pass cut-off filtering to perform efficient stimulation while actively suppressing stimulation artifacts in high-density microelectrode arrays. Owing to the dense packing and close proximity of the electrodes in such systems, a stimulation through one electrode can cause large electrical artifacts on neighboring electrodes that easily saturate the corresponding recording amplifiers. To suppress such artifacts, the high-pass corner frequencies of all available 2048 recording channels can be raised from several Hz to several kHz by applying a "soft-reset" or pole-shifting technique. With the implemented artifact suppression technique, the saturation time of the recording circuits, connected to electrodes in immediate vicinity to the stimulation site, could be reduced to less than 150μs. For the stimulation buffer, we developed a circuit, which can operate in two modes: either control of only the stimulation voltage, or control of current and voltage during stimulation. The voltage-only controlled mode employs a local common-mode feedback operational transconductance amplifier with a near rail-to-rail input/output range, suitable for driving high capacitive loads. The current/voltage controlled mode is based on a positive current conveyor generating adjustable output currents, while its upper and lower output voltages are limited by two feedback loops. The current/voltage controlled circuit can generate stimulation pulses up to 30 μA with less than ±0.1% linearity error in the low-current mode, and up to 300 μA with less than ±0.2% linearity error in the high-current mode. Close https://ieeexplore.ieee.org/document/8599003 doi:10.1109/TBME.2018.2890530 Close
2018
	Bakkum, Douglas J; Obien, Marie Engelene J; Radivojevic, Milos; Jäckel, David; Frey, Urs; Takahashi, Hirokazu; Hierlemann, Andreas The Axon Initial Segment is the Dominant Contributor to the Neuron's Extracellular Electrical Potential Landscape Journal Article Advanced Biosystems, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @article{Bakkum2018b, title = {The Axon Initial Segment is the Dominant Contributor to the Neuron's Extracellular Electrical Potential Landscape}, author = {Douglas J. Bakkum and Marie Engelene J. Obien and Milos Radivojevic and David Jäckel and Urs Frey and Hirokazu Takahashi and Andreas Hierlemann}, url = {https://onlinelibrary.wiley.com/doi/full/10.1002/adbi.201800308}, doi = {10.1002/adbi.201800308}, year = {2018}, date = {2018-11-29}, journal = {Advanced Biosystems}, abstract = {Extracellular voltage fields, produced by a neuron's action potentials, provide a widely used means for studying neuronal and neuronal‐network function. The neuron's soma and dendrites are thought to drive the extracellular action potential (EAP) landscape, while the axon's contribution is usually considered less important. However, by recording voltages of single neurons in dissociated rat cortical cultures and Purkinje cells in acute mouse cerebellar slices through hundreds of densely packed electrodes, it is found, instead, that the axon initial segment dominates the measured EAP landscape, and, surprisingly, the soma only contributes to a minor extent. As expected, the recorded dominant signal has negative polarity (charge entering the cell) and initiates at the distal end. Interestingly, signals with positive polarity (charge exiting the cell) occur near some but not all dendritic branches and occur after a delay. Such basic knowledge about which neuronal compartments contribute to the extracellular voltage landscape is important for interpreting results from all electrical readout schemes. Finally, initiation of the electrical activity at the distal end of the axon initial segment (AIS) and subsequent spreading into the axon proper and backward through the proximal AIS toward the soma are confirmed. The corresponding extracellular waveforms across different neuronal compartments could be tracked.}, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close Extracellular voltage fields, produced by a neuron's action potentials, provide a widely used means for studying neuronal and neuronal‐network function. The neuron's soma and dendrites are thought to drive the extracellular action potential (EAP) landscape, while the axon's contribution is usually considered less important. However, by recording voltages of single neurons in dissociated rat cortical cultures and Purkinje cells in acute mouse cerebellar slices through hundreds of densely packed electrodes, it is found, instead, that the axon initial segment dominates the measured EAP landscape, and, surprisingly, the soma only contributes to a minor extent. As expected, the recorded dominant signal has negative polarity (charge entering the cell) and initiates at the distal end. Interestingly, signals with positive polarity (charge exiting the cell) occur near some but not all dendritic branches and occur after a delay. Such basic knowledge about which neuronal compartments contribute to the extracellular voltage landscape is important for interpreting results from all electrical readout schemes. Finally, initiation of the electrical activity at the distal end of the axon initial segment (AIS) and subsequent spreading into the axon proper and backward through the proximal AIS toward the soma are confirmed. The corresponding extracellular waveforms across different neuronal compartments could be tracked. Close https://onlinelibrary.wiley.com/doi/full/10.1002/adbi.201800308 doi:10.1002/adbi.201800308 Close
	Lewandowska, Marta K; Bogatikov, Evgenii; Hierlemann, Andreas; Punga, Anna Rostedt Long-term high-density extracellular recordings enable studies of muscle cell physiology and pathology Conference Contribution 700.13 , Society for Neuroscience (SfN) Meeting San Diego, CA, USA, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Physiology @conference{Lewandowska2018c, title = {Long-term high-density extracellular recordings enable studies of muscle cell physiology and pathology}, author = {Marta K. Lewandowska and Evgenii Bogatikov and Andreas Hierlemann and Anna Rostedt Punga}, url = {https://abstractsonline.com/pp8/#!/4649/presentation/24936}, year = {2018}, date = {2018-11-07}, volume = {Contribution 700.13}, address = {San Diego, CA, USA}, organization = {Society for Neuroscience (SfN) Meeting}, abstract = {Skeletal (voluntary) muscle is the most abundant tissue in the body, thus making it an important biomedical research subject. Studies of neuromuscular transmission, including disorders of defective ion channels or receptors in autoimmune or genetic neuromuscular disorders, require high spatial resolution and an ability to acquire repeated recordings over time in order to track pharmacological interventions. Preclinical techniques for studying diseases of neuromuscular transmission can be enhanced by physiologic ex vivo models of tissue-tissue and cell-cell interactions. We present a method, which we used to follow the development of primary skeletal muscle cells from myoblasts into mature contracting myofibers over more than two months. In contrast to most previous studies, the muscles do not detach from the surface but instead form functional networks between the myofibers, whose electrical signals we observed over the entire culturing period. Primary cultures of mouse myoblasts differentiated into contracting myofibers on a chip that contains an array of 26,400 platinum electrodes at a density of 3,265 electrodes per mm2. Our ability to track extracellular action potentials at subcellular resolution enables discovery of the origin of possible failure mechanisms in muscle diseases. This system in turn enables creation of a novel electrophysiological platform for establishing ex vivo disease models.}, keywords = {ETH-CMOS-MEA, Physiology}, pubstate = {published}, tppubtype = {conference} } Close Skeletal (voluntary) muscle is the most abundant tissue in the body, thus making it an important biomedical research subject. Studies of neuromuscular transmission, including disorders of defective ion channels or receptors in autoimmune or genetic neuromuscular disorders, require high spatial resolution and an ability to acquire repeated recordings over time in order to track pharmacological interventions. Preclinical techniques for studying diseases of neuromuscular transmission can be enhanced by physiologic ex vivo models of tissue-tissue and cell-cell interactions. We present a method, which we used to follow the development of primary skeletal muscle cells from myoblasts into mature contracting myofibers over more than two months. In contrast to most previous studies, the muscles do not detach from the surface but instead form functional networks between the myofibers, whose electrical signals we observed over the entire culturing period. Primary cultures of mouse myoblasts differentiated into contracting myofibers on a chip that contains an array of 26,400 platinum electrodes at a density of 3,265 electrodes per mm2. Our ability to track extracellular action potentials at subcellular resolution enables discovery of the origin of possible failure mechanisms in muscle diseases. This system in turn enables creation of a novel electrophysiological platform for establishing ex vivo disease models. Close https://abstractsonline.com/pp8/#!/4649/presentation/24936 Close
	Emmenegger, Vishalini; Bartram, Julian; Sitnikov, Sergey; Hierlemann, Andreas Investigating the analog modulation of action-potential waveforms in axonal arbors of cortical neurons using whole-cell patch-clamp recordings and high-density microelectrode arrays Conference Contribution 203.05 , Society for Neuroscience (SfN) Meeting, San Diego, CA, USA, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @conference{Emmenegger2018, title = {Investigating the analog modulation of action-potential waveforms in axonal arbors of cortical neurons using whole-cell patch-clamp recordings and high-density microelectrode arrays}, author = {Vishalini Emmenegger and Julian Bartram and Sergey Sitnikov and Andreas Hierlemann}, url = {https://abstractsonline.com/pp8/#!/4649/presentation/9323}, year = {2018}, date = {2018-11-04}, volume = {Contribution 203.05}, publisher = {Society for Neuroscience (SfN) Meeting}, address = {San Diego, CA, USA}, abstract = {Analog-digital facilitation (ADF) is a type of short-term plasticity, where the subthreshold membrane potential in the presynaptic element enhances the spike-evoked synaptic response. Most cases of ADF have been induced by long (0.3-10 s) subthreshold depolarization of the soma, while in few cases, transient (15-200 ms) hyperpolarization has been evoked immediately before the action potential (AP). In both cases, somatic membrane fluctuations modulate the biophysical properties of voltage-gated ion channels causing changes in the AP waveform, which result in larger release of neurotransmitters. However, it is still unknown, whether the modulation of the AP waveform changes with increasing distance from the soma and differs in different axonal arbors, and whether such modulation affects the velocity of AP propagation. Here, we used CMOS-based high-density microelectrode arrays (HD-MEA) with 26,400 microelectrodes, which enabled unprecedented high-resolution access to investigating axonal signaling at multiple sites simultaneously, thus providing in-depth information on the propagation of AP. The subthreshold depolarization and hyperpolarization of the presynaptic cell was performed using whole-cell patch-clamp recordings from cells in low-density cortical cultures, plated on a HD-MEA that allowed to trace the effects of such manipulations on AP propagation characteristics. Array-wide spike-triggered average signals were computed, and their spatiotemporal distribution was reconstructed. In order to study the changes in extracellular AP waveforms, we first induced pharmacological modulations using dendrotoxin and carbamazepine, which increased AP width and amplitude. As a next step, we evoked AP broadening and amplitude changes by subthreshold depolarization and hyperpolarization. We detected the extracellular AP waveforms directly under the soma and traced them throughout the axon during various time spans and for different holding potentials. We found that changes in AP propagation velocity were correlated to the detected AP broadening. Our preliminary data evidenced changes in AP waveforms with increasing distance from the soma along the axon, but further experiments on synaptically coupled neurons using paired recordings will be performed to better understand the influence of AP modulation on ADF. Information encoding in neuronal circuits is probably contingent on both, temporal spike patterns and spike waveforms. In the light of the latter being typically disregarded in computational models, the study of the analog modulation of AP waveforms will contribute to a better understanding of neuronal information processing.}, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {conference} } Close Analog-digital facilitation (ADF) is a type of short-term plasticity, where the subthreshold membrane potential in the presynaptic element enhances the spike-evoked synaptic response. Most cases of ADF have been induced by long (0.3-10 s) subthreshold depolarization of the soma, while in few cases, transient (15-200 ms) hyperpolarization has been evoked immediately before the action potential (AP). In both cases, somatic membrane fluctuations modulate the biophysical properties of voltage-gated ion channels causing changes in the AP waveform, which result in larger release of neurotransmitters. However, it is still unknown, whether the modulation of the AP waveform changes with increasing distance from the soma and differs in different axonal arbors, and whether such modulation affects the velocity of AP propagation. Here, we used CMOS-based high-density microelectrode arrays (HD-MEA) with 26,400 microelectrodes, which enabled unprecedented high-resolution access to investigating axonal signaling at multiple sites simultaneously, thus providing in-depth information on the propagation of AP. The subthreshold depolarization and hyperpolarization of the presynaptic cell was performed using whole-cell patch-clamp recordings from cells in low-density cortical cultures, plated on a HD-MEA that allowed to trace the effects of such manipulations on AP propagation characteristics. Array-wide spike-triggered average signals were computed, and their spatiotemporal distribution was reconstructed. In order to study the changes in extracellular AP waveforms, we first induced pharmacological modulations using dendrotoxin and carbamazepine, which increased AP width and amplitude. As a next step, we evoked AP broadening and amplitude changes by subthreshold depolarization and hyperpolarization. We detected the extracellular AP waveforms directly under the soma and traced them throughout the axon during various time spans and for different holding potentials. We found that changes in AP propagation velocity were correlated to the detected AP broadening. Our preliminary data evidenced changes in AP waveforms with increasing distance from the soma along the axon, but further experiments on synaptically coupled neurons using paired recordings will be performed to better understand the influence of AP modulation on ADF. Information encoding in neuronal circuits is probably contingent on both, temporal spike patterns and spike waveforms. In the light of the latter being typically disregarded in computational models, the study of the analog modulation of AP waveforms will contribute to a better understanding of neuronal information processing. Close https://abstractsonline.com/pp8/#!/4649/presentation/9323 Close
	Ronchi, Silvia; Fiscella, Michele; Marchetti, Camilla; Viswam, Vijay; Müller, Jan; Frey, Urs; Hierlemann, Andreas Single-neuron sub-cellular-resolution electrical stimulation with high-density microelectrode arrays Conference Contribution 174.05 , Society for Neuroscience (SfN) Meeting San Diego, CA, USA, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Stimulation @conference{Ronchi2018, title = {Single-neuron sub-cellular-resolution electrical stimulation with high-density microelectrode arrays}, author = {Silvia Ronchi and Michele Fiscella and Camilla Marchetti and Vijay Viswam and Jan Müller and Urs Frey and Andreas Hierlemann}, url = {https://abstractsonline.com/pp8/#!/4649/presentation/24382}, year = {2018}, date = {2018-11-04}, volume = {Contribution 174.05}, address = {San Diego, CA, USA}, organization = {Society for Neuroscience (SfN) Meeting}, abstract = {Non-invasive electrical stimulation is a consolidated technique to study and control neural activity in the brain and peripheral nervous system. It is used, e.g., for controlling Parkinson's disease or to induce sensation in paralyzed patients (Armenta Salas et al., 2018), as well as for attempts to restore vision (Fan et al., 2018; Grosberg et al., 2017) and hearing (Wilson & Dorman, 2008). A common requirement in electrical stimulation is the precise and controlled stimulation of individual targeted neurons. For achieving this purpose, it is necessary that electrodes can stimulate and record extracellular signals at sub-cellular resolution. Furthermore, it is important to design efficient stimulation pulses to be delivered to the neurons. In the present work we used an CMOS-based high-density microelectrode array (HD-MEA) (Ballini et al., 2014), featuring 26’400 bidirectional electrodes with a pitch of 17.5 µm, which was designed for in-vitro applications. This high-resolution was used to test electrical stimulation parameters in vitro, which then could potentially be adapted to elicit single-cell action potentials in vivo. In this work we used different stimulation parameters, such as waveforms, amplitudes and durations (Grosberg et al., 2017; Wagenaar, Pine, & Potter, 2004), using 5x9 µm² electrodes to target sub-cellular structures in single neurons. E-18 Wistar rat cortical neurons were stimulated at days-in-vitro 10, 15, 20 and 25 using randomized voltage and current stimulation modalities. Axon initial segments of individual neurons (Radivojevic et al., 2016) were targeted for stimulation, enabled by the HD-MEA device. We found that voltage biphasic anodic-cathodic waveforms were less efficient than biphasic cathodic-anodic waveforms in eliciting action potentials in a single neuron. Moreover, it was possible to detect action potentials directly at the cell soma, which ensured a reliable confirmation of successful neuron stimulation. Finally, HD-MEA technology enabled to elicit action potentials in single-neurons embedded in high-density cell cultures. The obtained results can be used to optimize in vivo single-cell targeting for stimulation and read-out.}, keywords = {ETH-CMOS-MEA, Stimulation}, pubstate = {published}, tppubtype = {conference} } Close Non-invasive electrical stimulation is a consolidated technique to study and control neural activity in the brain and peripheral nervous system. It is used, e.g., for controlling Parkinson's disease or to induce sensation in paralyzed patients (Armenta Salas et al., 2018), as well as for attempts to restore vision (Fan et al., 2018; Grosberg et al., 2017) and hearing (Wilson & Dorman, 2008). A common requirement in electrical stimulation is the precise and controlled stimulation of individual targeted neurons. For achieving this purpose, it is necessary that electrodes can stimulate and record extracellular signals at sub-cellular resolution. Furthermore, it is important to design efficient stimulation pulses to be delivered to the neurons. In the present work we used an CMOS-based high-density microelectrode array (HD-MEA) (Ballini et al., 2014), featuring 26’400 bidirectional electrodes with a pitch of 17.5 µm, which was designed for in-vitro applications. This high-resolution was used to test electrical stimulation parameters in vitro, which then could potentially be adapted to elicit single-cell action potentials in vivo. In this work we used different stimulation parameters, such as waveforms, amplitudes and durations (Grosberg et al., 2017; Wagenaar, Pine, & Potter, 2004), using 5x9 µm² electrodes to target sub-cellular structures in single neurons. E-18 Wistar rat cortical neurons were stimulated at days-in-vitro 10, 15, 20 and 25 using randomized voltage and current stimulation modalities. Axon initial segments of individual neurons (Radivojevic et al., 2016) were targeted for stimulation, enabled by the HD-MEA device. We found that voltage biphasic anodic-cathodic waveforms were less efficient than biphasic cathodic-anodic waveforms in eliciting action potentials in a single neuron. Moreover, it was possible to detect action potentials directly at the cell soma, which ensured a reliable confirmation of successful neuron stimulation. Finally, HD-MEA technology enabled to elicit action potentials in single-neurons embedded in high-density cell cultures. The obtained results can be used to optimize in vivo single-cell targeting for stimulation and read-out. Close https://abstractsonline.com/pp8/#!/4649/presentation/24382 Close
	Yuan, Xinyue; Emmenegger, Vishalini; Obien, Marie Engelene J; Hierlemann, Andreas; Frey, Urs Dual-Mode Microelectrode Array Featuring 20k Electrodes and High SNR for Extracellular Recording of Neural Networks Conference paper 6065 , IEEE Biomedical Circuits and Systems Conference (BioCAS) Cleveland, Ohio, USA, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @conference{Yuan2018b, title = {Dual-Mode Microelectrode Array Featuring 20k Electrodes and High SNR for Extracellular Recording of Neural Networks}, author = {Xinyue Yuan and Vishalini Emmenegger and Marie Engelene J. Obien and Andreas Hierlemann and Urs Frey}, url = {https://www.epapers.org/biocas2018/ESR/paper_details.php?PHPSESSID=ok076vdjtkiu7kett65d8hk0g0&paper_id=6056}, year = {2018}, date = {2018-10-17}, volume = {paper 6065}, address = {Cleveland, Ohio, USA}, organization = {IEEE Biomedical Circuits and Systems Conference (BioCAS)}, abstract = {In recent electrophysiological studies, CMOS-based high-density microelectrode arrays (HD-MEA) have been widely used for studies of both in-vitro and in-vivo neuronal signals and network behavior. Yet, an open issue in MEA design concerns the tradeoff between signal-to-noise ratio (SNR) and number of readout channels. Here we present a new HD-MEA design in 0.18 μm CMOS technology, consisting of 19,584 electrodes at a pitch of 18.0 μm. By combing two readout structures,namely active-pixel-sensor (APS) and switch-matrix (SM) on a single chip, the dual-mode HD-MEA is capable of recording simultaneously from the entire array and achieving high signal-to-noise-ratio recordings on a subset of electrodes. The APS readout circuits feature a noise level of 10.9 μVrms for the action potential band (300 Hz - 5 kHz), while the noise level for the switch-matrix readout is 3.1 μVrms. }, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {conference} } Close In recent electrophysiological studies, CMOS-based high-density microelectrode arrays (HD-MEA) have been widely used for studies of both in-vitro and in-vivo neuronal signals and network behavior. Yet, an open issue in MEA design concerns the tradeoff between signal-to-noise ratio (SNR) and number of readout channels. Here we present a new HD-MEA design in 0.18 μm CMOS technology, consisting of 19,584 electrodes at a pitch of 18.0 μm. By combing two readout structures,namely active-pixel-sensor (APS) and switch-matrix (SM) on a single chip, the dual-mode HD-MEA is capable of recording simultaneously from the entire array and achieving high signal-to-noise-ratio recordings on a subset of electrodes. The APS readout circuits feature a noise level of 10.9 μVrms for the action potential band (300 Hz - 5 kHz), while the noise level for the switch-matrix readout is 3.1 μVrms. Close https://www.epapers.org/biocas2018/ESR/paper_details.php?PHPSESSID=ok076vdjtkiu7[...] Close
	Lewandowska, Marta K; Bogatikov, Evgenii; Hierlemann, Andreas; Punga, Anna Rostedt Long-Term High-Density Extracellular Recordings Enable Studies of Muscle Cell Physiology Journal Article Frontiers in Physiology, 9 , 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Muscle @article{Lewandowska2018cb, title = {Long-Term High-Density Extracellular Recordings Enable Studies of Muscle Cell Physiology }, author = {Marta K. Lewandowska and Evgenii Bogatikov and Andreas Hierlemann and Anna Rostedt Punga}, url = {https://www.frontiersin.org/article/10.3389/fphys.2018.01424 }, doi = {10.3389/fphys.2018.01424}, year = {2018}, date = {2018-10-09}, journal = {Frontiers in Physiology}, volume = {9}, abstract = {Skeletal (voluntary) muscle is the most abundant tissue in the body, thus making it an important biomedical research subject. Studies of neuromuscular transmission, including disorders of ion channels or receptors in autoimmune or genetic neuromuscular disorders, require high-spatial-resolution measurement techniques and an ability to acquire repeated recordings over time in order to track pharmacological interventions. Preclinical techniques for studying diseases of neuromuscular transmission can be enhanced by physiologic ex vivo models of tissue-tissue and cell-cell interactions. Here, we present a method, which allows tracking the development of primary skeletal muscle cells from myoblasts into mature contracting myotubes over more than 2 months. In contrast to most previous studies, the myotubes did not detach from the surface but instead formed functional networks between the myotubes, whose electrical signals were observed over the entire culturing period. Primary cultures of mouse myoblasts differentiated into contracting myotubes on a chip that contained an array of 26,400 platinum electrodes at a density of 3,265 electrodes per mm2. Our ability to track extracellular action potentials at subcellular resolution enabled study of skeletal muscle development and kinetics, modes of spiking and spatio-temporal relationships between muscles. The developed system in turn enables creation of a novel electrophysiological platform for establishing ex vivo disease models. }, keywords = {ETH-CMOS-MEA, Muscle}, pubstate = {published}, tppubtype = {article} } Close Skeletal (voluntary) muscle is the most abundant tissue in the body, thus making it an important biomedical research subject. Studies of neuromuscular transmission, including disorders of ion channels or receptors in autoimmune or genetic neuromuscular disorders, require high-spatial-resolution measurement techniques and an ability to acquire repeated recordings over time in order to track pharmacological interventions. Preclinical techniques for studying diseases of neuromuscular transmission can be enhanced by physiologic ex vivo models of tissue-tissue and cell-cell interactions. Here, we present a method, which allows tracking the development of primary skeletal muscle cells from myoblasts into mature contracting myotubes over more than 2 months. In contrast to most previous studies, the myotubes did not detach from the surface but instead formed functional networks between the myotubes, whose electrical signals were observed over the entire culturing period. Primary cultures of mouse myoblasts differentiated into contracting myotubes on a chip that contained an array of 26,400 platinum electrodes at a density of 3,265 electrodes per mm2. Our ability to track extracellular action potentials at subcellular resolution enabled study of skeletal muscle development and kinetics, modes of spiking and spatio-temporal relationships between muscles. The developed system in turn enables creation of a novel electrophysiological platform for establishing ex vivo disease models. Close https://www.frontiersin.org/article/10.3389/fphys.2018.01424 doi:10.3389/fphys.2018.01424 Close
	Ronchi, Silvia; Fiscella, Michele; Muller, Jan; Viswam, Vijay; Frey, Urs; Hierlemann, Andreas Single-cell electrical stimulation with CMOS-based high-density microelectrode arrays Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Stimulation @conference{Ronchi2018b, title = {Single-cell electrical stimulation with CMOS-based high-density microelectrode arrays}, author = {Silvia Ronchi and Michele Fiscella and Jan Muller and Vijay Viswam and Urs Frey and Andreas Hierlemann}, url = {https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00086/event_abstract}, doi = {10.3389/conf.fncel.2018.38.00086}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {The main goal of this work was to explore electrical stimulation parameters that reproducibly and precisely elicit action potentials in single neurons (Wagenaar et al. 2004). We compared voltage and current modalities’ and their efficacy in activating single neurons; we also studied the related stimulation artifacts. For our studies, we used a CMOS-based MEA featuring 26400 electrodes at 17.5 µm pitch (Ballini et al. 2014). }, keywords = {ETH-CMOS-MEA, Stimulation}, pubstate = {published}, tppubtype = {conference} } Close The main goal of this work was to explore electrical stimulation parameters that reproducibly and precisely elicit action potentials in single neurons (Wagenaar et al. 2004). We compared voltage and current modalities’ and their efficacy in activating single neurons; we also studied the related stimulation artifacts. For our studies, we used a CMOS-based MEA featuring 26400 electrodes at 17.5 µm pitch (Ballini et al. 2014). Close https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00086/event_abstract doi:10.3389/conf.fncel.2018.38.00086 Close
	Obien, Marie Engelene J; Zorzi, Giulio; Fiscella, Michele; Leary, Noelle; Hierlemann, Andreas Comparison of axonal-conduction velocity in developing primary cells and human iPSC-derived neurons Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MaxOne @conference{Obien2018, title = {Comparison of axonal-conduction velocity in developing primary cells and human iPSC-derived neurons}, author = {Marie Engelene J. Obien and Giulio Zorzi and Michele Fiscella and Noelle Leary and Andreas Hierlemann}, url = {https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00095/event_abstract}, doi = {10.3389/conf.fncel.2018.38.00095}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {Neurons communicate through action potentials propagating along axons. In developing cell cultures, axonal arbor outgrowth indicates the formation of synaptic connections between neurons, which form networks. As axons regulate the transfer of information, we hypothesize that axonal conduction characteristics, e.g., axonal action potential amplitude and propagation velocity, may be indicative of the maturation state of cells and the strength of interneuronal connections.}, keywords = {ETH-CMOS-MEA, MaxOne}, pubstate = {published}, tppubtype = {conference} } Close Neurons communicate through action potentials propagating along axons. In developing cell cultures, axonal arbor outgrowth indicates the formation of synaptic connections between neurons, which form networks. As axons regulate the transfer of information, we hypothesize that axonal conduction characteristics, e.g., axonal action potential amplitude and propagation velocity, may be indicative of the maturation state of cells and the strength of interneuronal connections. Close https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00095/event_abstract doi:10.3389/conf.fncel.2018.38.00095 Close
	Zorzi, Giulio; Obien, Marie Engelene J; Fiscella, Michele; Leary, Noelle; Hierlemann, Andreas Automatic extraction of axonal arbor morphology applied to h-iPSC-derived neurons Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MaxOne @conference{Zorzi2018, title = {Automatic extraction of axonal arbor morphology applied to h-iPSC-derived neurons}, author = {Giulio Zorzi and Marie Engelene J. Obien and Michele Fiscella and Noelle Leary and Andreas Hierlemann}, url = {https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00049/event_abstract}, doi = {10.3389/conf.fncel.2018.38.00049}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {Neurons derived from human induced pluripotent stem cells (h-iPSCs) offer tremendous opportunities to investigate the mechanisms involved in brain function and to model neurodegenerative diseases. Analyzing the behavior of h-iPSC-derived neurons that represent the phenotypes of human neurological disorders paves the way for the development of physiologically-relevant models and assays for drug discovery. In this framework, we utilize a CMOS-based high-density microelectrode array (HD-MEA, MaxWell Biosystems) to investigate h-iPSC neurons at sub-cellular resolution. Recording extracellular action potentials (EAPs or spikes) of cultured neurons through microelectrode arrays (MEAs) is a well-established technique for extracting valuable features of neuronal function and network connectivity (Obien et al., Frontiers in Neuroscience, 2015). }, keywords = {ETH-CMOS-MEA, MaxOne}, pubstate = {published}, tppubtype = {conference} } Close Neurons derived from human induced pluripotent stem cells (h-iPSCs) offer tremendous opportunities to investigate the mechanisms involved in brain function and to model neurodegenerative diseases. Analyzing the behavior of h-iPSC-derived neurons that represent the phenotypes of human neurological disorders paves the way for the development of physiologically-relevant models and assays for drug discovery. In this framework, we utilize a CMOS-based high-density microelectrode array (HD-MEA, MaxWell Biosystems) to investigate h-iPSC neurons at sub-cellular resolution. Recording extracellular action potentials (EAPs or spikes) of cultured neurons through microelectrode arrays (MEAs) is a well-established technique for extracting valuable features of neuronal function and network connectivity (Obien et al., Frontiers in Neuroscience, 2015). Close https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00049/event_abstract doi:10.3389/conf.fncel.2018.38.00049 Close
	Bounik, Raziyeh; Gusmaroli, Massimiliano; Viswam, Vijay; Modena, Mario M; Hierlemann, Andreas COMSOL modeling of an integrated impedance sensor in a hanging-drop platform Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Microtissue @conference{Bounik2018, title = {COMSOL modeling of an integrated impedance sensor in a hanging-drop platform}, author = {Raziyeh Bounik and Massimiliano Gusmaroli and Vijay Viswam and Mario M. Modena and Andreas Hierlemann}, url = {https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00083/event_abstract}, doi = {10.3389/conf.fncel.2018.38.00083}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {Traditional dish-based, two-dimensional cell cultures have limited prediction capability for drug testing, whereas three-dimensional spherical microtissues (spheroids) and organoids much more accurately replicate physiological conditions of cells in the respective tissue [1,2]. Such spheroids can be formed and cultured in microphysiological multi-tissue formats by using the hanging-drop technology as depicted in Fig. 1 [3]. Like most other microfluidic platforms, the hanging-drop platform still requires a microscope for visual inspection and considerable time for doing off-line measurements, as the spheroids/media have to be harvested from the microfluidic device for labeling and chemical analysis. It would be beneficial to have an integrated on-line multi-functional sensor as an additional readout, located directly at the tissue sites in the hanging-drop platform, so that measurements can be performed in situ and without harvesting medium or the tissue and without interrupting the overall culturing process. }, keywords = {ETH-CMOS-MEA, Microtissue}, pubstate = {published}, tppubtype = {conference} } Close Traditional dish-based, two-dimensional cell cultures have limited prediction capability for drug testing, whereas three-dimensional spherical microtissues (spheroids) and organoids much more accurately replicate physiological conditions of cells in the respective tissue [1,2]. Such spheroids can be formed and cultured in microphysiological multi-tissue formats by using the hanging-drop technology as depicted in Fig. 1 [3]. Like most other microfluidic platforms, the hanging-drop platform still requires a microscope for visual inspection and considerable time for doing off-line measurements, as the spheroids/media have to be harvested from the microfluidic device for labeling and chemical analysis. It would be beneficial to have an integrated on-line multi-functional sensor as an additional readout, located directly at the tissue sites in the hanging-drop platform, so that measurements can be performed in situ and without harvesting medium or the tissue and without interrupting the overall culturing process. Close https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00083/event_abstract doi:10.3389/conf.fncel.2018.38.00083 Close
	Yuan, Xinyue; Hierlemann, Andreas; Frey, Urs Dual-mode Microelectrode Array with 20k-electrodes and High SNR for High-Throughput Extracellular Recording and Stimulation Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Stimulation @conference{Yuan2018, title = {Dual-mode Microelectrode Array with 20k-electrodes and High SNR for High-Throughput Extracellular Recording and Stimulation}, author = {Xinyue Yuan and Andreas Hierlemann and Urs Frey}, url = {https://https://www.frontiersin.org/Community/AbstractDetails.aspx?ABS_DOI=10.3389/conf.fncel.2018.38.00088&eid=5473&sname=MEA_Meeting_2018_%7C_11th_International_Meeting_on_Substrate_Integrated_Microelectrode_Arrays}, doi = {10.3389/conf.fncel.2018.38.00088}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {Recording and analysis of neuronal signals can provide much insight into how neurons process information and communicate with each other. Recent advancements of microelectrode-array (MEA) technology provide unprecedented means to study neuronal signals and network behavior in in vitro and in vivo applications [1], [2]. The trade-off between noise performance, power consumption and electrode density, however, remains a major challenge in MEA design. To balance this tradeoff, we designed a Dual-mode (DM) MEA that combines two major types of readout schemes, i.e., the active-pixel-sensor (APS) and switch-matrix (SM) schemes, in order to achieve high electrode density and high signal-to-noise ratio (SNR) at the same time. Based on a previous prototype [3], the new DM-MEA has shown to be a useful tool for in-vitro neuroscience studies, especially for network studies}, keywords = {ETH-CMOS-MEA, Stimulation}, pubstate = {published}, tppubtype = {conference} } Close Recording and analysis of neuronal signals can provide much insight into how neurons process information and communicate with each other. Recent advancements of microelectrode-array (MEA) technology provide unprecedented means to study neuronal signals and network behavior in in vitro and in vivo applications [1], [2]. The trade-off between noise performance, power consumption and electrode density, however, remains a major challenge in MEA design. To balance this tradeoff, we designed a Dual-mode (DM) MEA that combines two major types of readout schemes, i.e., the active-pixel-sensor (APS) and switch-matrix (SM) schemes, in order to achieve high electrode density and high signal-to-noise ratio (SNR) at the same time. Based on a previous prototype [3], the new DM-MEA has shown to be a useful tool for in-vitro neuroscience studies, especially for network studies Close https://https://www.frontiersin.org/Community/AbstractDetails.aspx?ABS_DOI=10.33[...] doi:10.3389/conf.fncel.2018.38.00088 Close
	Bakkum Douglas J; Radivojevic, Milos; Obien Marie Engelene; Jaeckel David; Frey Urs; Takahashi Hirokazu; Hierlemann Andreas The axon initial segment drives the neuron's extracellular action potential Journal Article bioRxiv, pp. 1-30, 2018. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @article{Bakkum2018, title = {The axon initial segment drives the neuron's extracellular action potential}, author = {Bakkum, Douglas J; Radivojevic, Milos; Obien, Marie Engelene; Jaeckel, David; Frey, Urs; Takahashi, Hirokazu; Hierlemann, Andreas }, url = {https://www.biorxiv.org/content/early/2018/02/16/266734}, doi = {10.1101/266734 }, year = {2018}, date = {2018-02-16}, journal = {bioRxiv}, pages = {1-30}, abstract = {Extracellular voltage fields produced by a neuron's action potentials provide a primary means for studying neuron function, yet their biophysical sources remain ambiguous. The neuron's soma and dendrites are thought to drive the extracellular action potential (EAP), while the axon is usually ignored. However, by recording voltages of single neurons in dissociated rat cortical cultures and Purkinje cells in acute mouse cerebellar slices at hundreds of sites, we find instead that the axon initial segment dominates the EAP, and, surprisingly, the soma shows little or no influence. As expected, this signal has negative polarity (charge entering the cell) and initiates at the distal end. Interestingly, signals with positive polarity (charge exiting the cell) occur near some but not all dendritic branches and occur after a delay. Such basic knowledge about which neuronal compartments contribute to the extracellular voltage field is important for interpreting results from all electrical readout schemes. Moreover, this finding shows that changes in the AIS position and function can be observed in high spatiotemporal detail by means of high-density extracellular electrophysiology.}, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close Extracellular voltage fields produced by a neuron's action potentials provide a primary means for studying neuron function, yet their biophysical sources remain ambiguous. The neuron's soma and dendrites are thought to drive the extracellular action potential (EAP), while the axon is usually ignored. However, by recording voltages of single neurons in dissociated rat cortical cultures and Purkinje cells in acute mouse cerebellar slices at hundreds of sites, we find instead that the axon initial segment dominates the EAP, and, surprisingly, the soma shows little or no influence. As expected, this signal has negative polarity (charge entering the cell) and initiates at the distal end. Interestingly, signals with positive polarity (charge exiting the cell) occur near some but not all dendritic branches and occur after a delay. Such basic knowledge about which neuronal compartments contribute to the extracellular voltage field is important for interpreting results from all electrical readout schemes. Moreover, this finding shows that changes in the AIS position and function can be observed in high spatiotemporal detail by means of high-density extracellular electrophysiology. Close https://www.biorxiv.org/content/early/2018/02/16/266734 doi:10.1101/266734 Close
2017
	Radivojevic, Milos; Franke, Felix; Altermatt, Michael; Müller, Jan; Hierlemann, Andreas; Bakkum, Douglas J Tracking individual action potentials throughout mammalian axonal arbors Journal Article eLife, 6 , pp. 1-23, 2017, ISSN: 2050-084X. Abstract \| Links \| BibTeX \| Tags: Data Analysis, ETH-CMOS-MEA, Neuronal Networks, Stimulation @article{Radivojevic2017, title = {Tracking individual action potentials throughout mammalian axonal arbors}, author = {Milos Radivojevic and Felix Franke and Michael Altermatt and Jan Müller and Andreas Hierlemann and Douglas J Bakkum}, url = {https://elifesciences.org/articles/30198}, doi = {10.7554/eLife.30198}, issn = {2050-084X}, year = {2017}, date = {2017-10-09}, journal = {eLife}, volume = {6}, pages = {1-23}, abstract = {Axons are neuronal processes specialized for conduction of action potentials (APs). The timing and temporal precision of APs when they reach each of the synapses are fundamentally important for information processing in the brain. Due to small diameters of axons, direct recording of single AP transmission is challenging. Consequently, most knowledge about axonal conductance derives from modeling studies or indirect measurements. We demonstrate a method to noninvasively and directly record individual APs propagating along millimeter-length axonal arbors in cortical cultures with hundreds of microelectrodes at microsecond temporal resolution. We find that cortical axons conduct single APs with high temporal precision (~100 µs arrival time jitter per mm length) and reliability: in more than 8,000,000 recorded APs, we did not observe any conduction or branch-point failures. Upon high-frequency stimulation at 100 Hz, successive became slower, and their arrival time precision decreased by 20% and 12% for the 100th AP, respectively.}, keywords = {Data Analysis, ETH-CMOS-MEA, Neuronal Networks, Stimulation}, pubstate = {published}, tppubtype = {article} } Close Axons are neuronal processes specialized for conduction of action potentials (APs). The timing and temporal precision of APs when they reach each of the synapses are fundamentally important for information processing in the brain. Due to small diameters of axons, direct recording of single AP transmission is challenging. Consequently, most knowledge about axonal conductance derives from modeling studies or indirect measurements. We demonstrate a method to noninvasively and directly record individual APs propagating along millimeter-length axonal arbors in cortical cultures with hundreds of microelectrodes at microsecond temporal resolution. We find that cortical axons conduct single APs with high temporal precision (~100 µs arrival time jitter per mm length) and reliability: in more than 8,000,000 recorded APs, we did not observe any conduction or branch-point failures. Upon high-frequency stimulation at 100 Hz, successive became slower, and their arrival time precision decreased by 20% and 12% for the 100th AP, respectively. Close https://elifesciences.org/articles/30198 doi:10.7554/eLife.30198 Close
	Viswam, Vijay; Bounik, Raziyeh; Shadmani, Amir; Dragas, Jelena; Obien, Marie Engelene J; Muller, Jan; Chen, Yihui; Hierlemann, Andreas High-density Mapping of Brain Slices Using a Large Multi-functional High-density CMOS Microelectrode Array System Conference 19th International Conference on Solid-State Sensors, Actuators and Microsystems (TRANSDUCERS) Kaohsiung, Taiwan, 2017, ISSN: 2167-0021. Abstract \| Links \| BibTeX \| Tags: Brain Slice, ETH-CMOS-MEA, HD-MEA @conference{Viswam2017b, title = {High-density Mapping of Brain Slices Using a Large Multi-functional High-density CMOS Microelectrode Array System}, author = {Vijay Viswam and Raziyeh Bounik and Amir Shadmani and Jelena Dragas and Marie Engelene J. Obien and Jan Muller and Yihui Chen and Andreas Hierlemann }, url = {https://ieeexplore.ieee.org/abstract/document/7994006}, doi = {10.1109/TRANSDUCERS.2017.7994006}, issn = {2167-0021}, year = {2017}, date = {2017-06-18}, pages = {135-138}, address = {Kaohsiung, Taiwan}, organization = {19th International Conference on Solid-State Sensors, Actuators and Microsystems (TRANSDUCERS)}, abstract = {We present a CMOS-based high-density microelectrode array (HD-MEA) system that enables high-density mapping of brain slices in-vitro with multiple readout modalities. The 4.48×2.43 mm 2 array consists of 59,760 micro-electrodes at 13.5 μm pitch (5487 electrodes/mm 2 ). The overall system features 2048 action-potential, 32 local-field-potential and 32 current recording channels, 32 impedance-measurement and 28 neurotransmitter-detection channels and 16 voltage/current stimulation channels. The system enables real-time and label-free monitoring of position, size, morphology and electrical activity of brain slices.}, keywords = {Brain Slice, ETH-CMOS-MEA, HD-MEA}, pubstate = {published}, tppubtype = {conference} } Close We present a CMOS-based high-density microelectrode array (HD-MEA) system that enables high-density mapping of brain slices in-vitro with multiple readout modalities. The 4.48×2.43 mm 2 array consists of 59,760 micro-electrodes at 13.5 μm pitch (5487 electrodes/mm 2 ). The overall system features 2048 action-potential, 32 local-field-potential and 32 current recording channels, 32 impedance-measurement and 28 neurotransmitter-detection channels and 16 voltage/current stimulation channels. The system enables real-time and label-free monitoring of position, size, morphology and electrical activity of brain slices. Close https://ieeexplore.ieee.org/abstract/document/7994006 doi:10.1109/TRANSDUCERS.2017.7994006 Close
	Bullmann Torsten; Radivojevic, Milos; Huber Stefan Deligkaris Kosmas; Hierlemann Andreas; Frey Urs T: Network Analysis Of High-Density Microelectrode Recordings Journal Article bioRxiv , (139436), pp. 1-23, 2017. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @article{Bullmann2017, title = {Network Analysis Of High-Density Microelectrode Recordings}, author = {Bullmann, Torsten; Radivojevic, Milos; Huber, Stefan T: Deligkaris, Kosmas; Hierlemann, Andreas; Frey, Urs }, url = {https://www.biorxiv.org/content/early/2017/05/18/139436 }, doi = {10.1101/139436}, year = {2017}, date = {2017-05-18}, journal = {bioRxiv }, number = {139436}, pages = {1-23}, abstract = {Extracellular voltage fields produced by a neuron's action potentials provide a primary means for studying neuron function, yet their biophysical sources remain ambiguous. The neuron's soma and dendrites are thought to drive the extracellular action potential (EAP), while the axon is usually ignored. However, by recording voltages of single neurons in dissociated rat cortical cultures and Purkinje cells in acute mouse cerebellar slices at hundreds of sites, we find instead that the axon initial segment dominates the EAP, and, surprisingly, the soma shows little or no influence. As expected, this signal has negative polarity (charge entering the cell) and initiates at the distal end. Interestingly, signals with positive polarity (charge exiting the cell) occur near some but not all dendritic branches and occur after a delay. Such basic knowledge about which neuronal compartments contribute to the extracellular voltage field is important for interpreting results from all electrical readout schemes. Moreover, this finding shows that changes in the AIS position and function can be observed in high spatiotemporal detail by means of high-density extracellular electrophysiology.}, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close Extracellular voltage fields produced by a neuron's action potentials provide a primary means for studying neuron function, yet their biophysical sources remain ambiguous. The neuron's soma and dendrites are thought to drive the extracellular action potential (EAP), while the axon is usually ignored. However, by recording voltages of single neurons in dissociated rat cortical cultures and Purkinje cells in acute mouse cerebellar slices at hundreds of sites, we find instead that the axon initial segment dominates the EAP, and, surprisingly, the soma shows little or no influence. As expected, this signal has negative polarity (charge entering the cell) and initiates at the distal end. Interestingly, signals with positive polarity (charge exiting the cell) occur near some but not all dendritic branches and occur after a delay. Such basic knowledge about which neuronal compartments contribute to the extracellular voltage field is important for interpreting results from all electrical readout schemes. Moreover, this finding shows that changes in the AIS position and function can be observed in high spatiotemporal detail by means of high-density extracellular electrophysiology. Close https://www.biorxiv.org/content/early/2017/05/18/139436 doi:10.1101/139436 Close
	Dragas, Jelena; Viswam, Vijay; Shadmani, Amir; Chen, Yihui; Bounik, Raziyeh; Stettler, Alexander; Radivojevic, Milos; Geissler, Sydney; Obien, Marie Engelene J; Müller, Jan; Hierlemann, Andreas A Multi-Functional Microelectrode Array Featuring 59760 Electrodes, 2048 Electrophysiology Channels, Stimulation, Impedance Measurement and Neurotransmitter Detection Channels Journal Article IEEE journal of solid-state circuits, 52 (6), pp. 1576-1590, 2017, ISSN: 0018-9200. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MEA Technology @article{Dragas2017, title = {A Multi-Functional Microelectrode Array Featuring 59760 Electrodes, 2048 Electrophysiology Channels, Stimulation, Impedance Measurement and Neurotransmitter Detection Channels}, author = {Jelena Dragas and Vijay Viswam and Amir Shadmani and Yihui Chen and Raziyeh Bounik and Alexander Stettler and Milos Radivojevic and Sydney Geissler and Marie Engelene J Obien and Jan Müller and Andreas Hierlemann}, url = {http://ieeexplore.ieee.org/document/7913669/}, doi = {10.1109/JSSC.2017.2686580}, issn = {0018-9200}, year = {2017}, date = {2017-04-27}, journal = {IEEE journal of solid-state circuits}, volume = {52}, number = {6}, pages = {1576-1590}, abstract = {Biological cells are characterized by highly complex phenomena and processes that are, to a great extent, interdependent. To gain detailed insights, devices designed to study cellular phenomena need to enable tracking and manipulation of multiple cell parameters in parallel; they have to provide high signal quality and high spatiotemporal resolution. To this end, we have developed a CMOS-based microelectrode array system that integrates six measurement and stimulation functions, the largest number to date. Moreover, the system features the largest active electrode array area to date (4.48×2.43 mm(2)) to accommodate 59,760 electrodes, while its power consumption, noise characteristics, and spatial resolution (13.5 mum electrode pitch) are comparable to the best state-of-the-art devices. The system includes: 2,048 action-potential (AP, bandwidth: 300 Hz to 10 kHz) recording units, 32 local-field-potential (LFP, bandwidth: 1 Hz to 300 Hz) recording units, 32 current recording units, 32 impedance measurement units, and 28 neurotransmitter detection units, in addition to the 16 dual-mode voltage-only or current/voltage-controlled stimulation units. The electrode array architecture is based on a switch matrix, which allows for connecting any measurement/stimulation unit to any electrode in the array and for performing different measurement/stimulation functions in parallel.}, keywords = {ETH-CMOS-MEA, MEA Technology}, pubstate = {published}, tppubtype = {article} } Close Biological cells are characterized by highly complex phenomena and processes that are, to a great extent, interdependent. To gain detailed insights, devices designed to study cellular phenomena need to enable tracking and manipulation of multiple cell parameters in parallel; they have to provide high signal quality and high spatiotemporal resolution. To this end, we have developed a CMOS-based microelectrode array system that integrates six measurement and stimulation functions, the largest number to date. Moreover, the system features the largest active electrode array area to date (4.48×2.43 mm(2)) to accommodate 59,760 electrodes, while its power consumption, noise characteristics, and spatial resolution (13.5 mum electrode pitch) are comparable to the best state-of-the-art devices. The system includes: 2,048 action-potential (AP, bandwidth: 300 Hz to 10 kHz) recording units, 32 local-field-potential (LFP, bandwidth: 1 Hz to 300 Hz) recording units, 32 current recording units, 32 impedance measurement units, and 28 neurotransmitter detection units, in addition to the 16 dual-mode voltage-only or current/voltage-controlled stimulation units. The electrode array architecture is based on a switch matrix, which allows for connecting any measurement/stimulation unit to any electrode in the array and for performing different measurement/stimulation functions in parallel. Close http://ieeexplore.ieee.org/document/7913669/ doi:10.1109/JSSC.2017.2686580 Close
	Jäckel, David; Bakkum, Douglas J; Russell, Thomas L; Müller, Jan; Radivojevic, Milos; Frey, Urs; Franke, Felix; Hierlemann, Andreas Combination of High-density Microelectrode Array and Patch Clamp Recordings to Enable Studies of Multisynaptic Integration Journal Article Scientific Reports, 7 (1), pp. 978, 2017, ISSN: 2045-2322. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks @article{Jackel2017, title = {Combination of High-density Microelectrode Array and Patch Clamp Recordings to Enable Studies of Multisynaptic Integration}, author = {David Jäckel and Douglas J Bakkum and Thomas L Russell and Jan Müller and Milos Radivojevic and Urs Frey and Felix Franke and Andreas Hierlemann}, url = {http://www.nature.com/articles/s41598-017-00981-4}, doi = {10.1038/s41598-017-00981-4}, issn = {2045-2322}, year = {2017}, date = {2017-04-20}, journal = {Scientific Reports}, volume = {7}, number = {1}, pages = {978}, abstract = {We present a novel, all-electric approach to record and to precisely control the activity of tens of individual presynaptic neurons. The method allows for parallel mapping of the efficacy of multiple synapses and of the resulting dynamics of postsynaptic neurons in a cortical culture. For the measurements, we combine an extracellular high-density microelectrode array, featuring 11'000 electrodes for extracellular recording and stimulation, with intracellular patch-clamp recording. We are able to identify the contributions of individual presynaptic neurons - including inhibitory and excitatory synaptic inputs - to postsynaptic potentials, which enables us to study dendritic integration. Since the electrical stimuli can be controlled at microsecond resolution, our method enables to evoke action potentials at tens of presynaptic cells in precisely orchestrated sequences of high reliability and minimum jitter. We demonstrate the potential of this method by evoking short- and long-term synaptic plasticity through manipulation of multiple synaptic inputs to a specific neuron.}, keywords = {ETH-CMOS-MEA, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close We present a novel, all-electric approach to record and to precisely control the activity of tens of individual presynaptic neurons. The method allows for parallel mapping of the efficacy of multiple synapses and of the resulting dynamics of postsynaptic neurons in a cortical culture. For the measurements, we combine an extracellular high-density microelectrode array, featuring 11'000 electrodes for extracellular recording and stimulation, with intracellular patch-clamp recording. We are able to identify the contributions of individual presynaptic neurons - including inhibitory and excitatory synaptic inputs - to postsynaptic potentials, which enables us to study dendritic integration. Since the electrical stimuli can be controlled at microsecond resolution, our method enables to evoke action potentials at tens of presynaptic cells in precisely orchestrated sequences of high reliability and minimum jitter. We demonstrate the potential of this method by evoking short- and long-term synaptic plasticity through manipulation of multiple synaptic inputs to a specific neuron. Close http://www.nature.com/articles/s41598-017-00981-4 doi:10.1038/s41598-017-00981-4 Close
	Seichepine, Florent; Rothe, Jorg; Dudina, Alexandra; Hierlemann, Andreas; Frey, Urs Dielectrophoresis‐Assisted Integration of 1024 Carbon Nanotube Sensors into a CMOS Microsystem Journal Article Advanced Materials, 29 (17), 2017. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA @article{Seichepine2017, title = {Dielectrophoresis‐Assisted Integration of 1024 Carbon Nanotube Sensors into a CMOS Microsystem}, author = {Florent Seichepine and Jorg Rothe and Alexandra Dudina and Andreas Hierlemann and Urs Frey}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/adma.201606852}, doi = {10.1002/adma.201606852}, year = {2017}, date = {2017-03-15}, journal = {Advanced Materials}, volume = {29}, number = {17}, abstract = {Carbon‐nanotube (CNT)‐based sensors offer the potential to detect single‐molecule events and picomolar analyte concentrations. An important step toward applications of such nanosensors is their integration in large arrays. The availability of large arrays would enable multiplexed and parallel sensing, and the simultaneously obtained sensor signals would facilitate statistical analysis. A reliable method to fabricate an array of 1024 CNT‐based sensors on a fully processed complementary‐metal‐oxide‐semiconductor microsystem is presented. A high‐yield process for the deposition of CNTs from a suspension by means of liquid‐coupled floating‐electrode dielectrophoresis (DEP), which yielded 80% of the sensor devices featuring between one and five CNTs, is developed. The mechanism of floating‐electrode DEP on full arrays and individual devices to understand its self‐limiting behavior is studied. The resistance distributions across the array of CNT devices with respect to different DEP parameters are characterized. The CNT devices are then operated as liquid‐gated CNT field‐effect‐transistors (LG‐CNTFET) in liquid environment. Current dependency to the gate voltage of up to two orders of magnitude is recorded. Finally, the sensors are validated by studying the pH dependency of the LG‐CNTFET conductance and it is demonstrated that 73% of the CNT sensors of a given microsystem show a resistance decrease upon increasing the pH value.}, keywords = {ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close Carbon‐nanotube (CNT)‐based sensors offer the potential to detect single‐molecule events and picomolar analyte concentrations. An important step toward applications of such nanosensors is their integration in large arrays. The availability of large arrays would enable multiplexed and parallel sensing, and the simultaneously obtained sensor signals would facilitate statistical analysis. A reliable method to fabricate an array of 1024 CNT‐based sensors on a fully processed complementary‐metal‐oxide‐semiconductor microsystem is presented. A high‐yield process for the deposition of CNTs from a suspension by means of liquid‐coupled floating‐electrode dielectrophoresis (DEP), which yielded 80% of the sensor devices featuring between one and five CNTs, is developed. The mechanism of floating‐electrode DEP on full arrays and individual devices to understand its self‐limiting behavior is studied. The resistance distributions across the array of CNT devices with respect to different DEP parameters are characterized. The CNT devices are then operated as liquid‐gated CNT field‐effect‐transistors (LG‐CNTFET) in liquid environment. Current dependency to the gate voltage of up to two orders of magnitude is recorded. Finally, the sensors are validated by studying the pH dependency of the LG‐CNTFET conductance and it is demonstrated that 73% of the CNT sensors of a given microsystem show a resistance decrease upon increasing the pH value. Close https://onlinelibrary.wiley.com/doi/abs/10.1002/adma.201606852 doi:10.1002/adma.201606852 Close
	Yada, Yuichiro; Mita, Takeshi; Sanada, Akihiro; Yano, Ryuichi; Kanzaki, Ryohei; Bakkum, Douglas J; Hierlemann, Andreas; Takahashi, Hirokazu Development of neural population activity toward self-organized criticality Journal Article Neuroscience, 343 , pp. 55-65, 2017, ISSN: 0306-4522. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks @article{Takahashi2017, title = {Development of neural population activity toward self-organized criticality}, author = {Yuichiro Yada and Takeshi Mita and Akihiro Sanada and Ryuichi Yano and Ryohei Kanzaki and Douglas J Bakkum and Andreas Hierlemann and Hirokazu Takahashi}, url = {http://www.sciencedirect.com/science/article/pii/S0306452216306522}, doi = {10.1016/j.neuroscience.2016.11.031}, issn = {0306-4522}, year = {2017}, date = {2017-02-20}, journal = {Neuroscience}, volume = {343}, pages = {55-65}, abstract = {Self-organized criticality (SoC), a spontaneous dynamic state established and maintained in networks of moderate complexity, is a universal characteristic of neural systems. Such systems produce cascades of spontaneous activity that are typically characterized by power-law distributions and rich, stable spatiotemporal patterns (i.e., neuronal avalanches). Since the dynamics of the critical state confer advantages in information processing within neuronal networks, it is of great interest to determine how criticality emerges during development. One possible mechanism is developmental, and includes axonal elongation during synaptogenesis and subsequent synaptic pruning in combination with the maturation of GABAergic inhibition (i.e., the integration then fragmentation process). Because experimental evidence for this mechanism remains inconclusive, we studied the developmental variation of neuronal avalanches in dissociated cortical neurons using high-density complementary metal-oxide semiconductor (CMOS) microelectrode arrays (MEAs). The spontaneous activities of nine cultures were monitored using CMOS MEAs from 4 to 30 days in vitro (DIV) at single-cell spatial resolution. While cells were immature, cultures demonstrated random-like patterns of activity and an exponential avalanche size distribution; this distribution was followed by a bimodal distribution, and finally a power-law-like distribution. The bimodal distribution was associated with a large-scale avalanche with a homogeneous spatiotemporal pattern, while the subsequent power-law distribution was associated with diverse patterns. These results suggest that the SoC emerges through a two-step process: the integration process accompanying the characteristic large-scale avalanche and the fragmentation process associated with diverse middle-size avalanches.}, keywords = {ETH-CMOS-MEA, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close Self-organized criticality (SoC), a spontaneous dynamic state established and maintained in networks of moderate complexity, is a universal characteristic of neural systems. Such systems produce cascades of spontaneous activity that are typically characterized by power-law distributions and rich, stable spatiotemporal patterns (i.e., neuronal avalanches). Since the dynamics of the critical state confer advantages in information processing within neuronal networks, it is of great interest to determine how criticality emerges during development. One possible mechanism is developmental, and includes axonal elongation during synaptogenesis and subsequent synaptic pruning in combination with the maturation of GABAergic inhibition (i.e., the integration then fragmentation process). Because experimental evidence for this mechanism remains inconclusive, we studied the developmental variation of neuronal avalanches in dissociated cortical neurons using high-density complementary metal-oxide semiconductor (CMOS) microelectrode arrays (MEAs). The spontaneous activities of nine cultures were monitored using CMOS MEAs from 4 to 30 days in vitro (DIV) at single-cell spatial resolution. While cells were immature, cultures demonstrated random-like patterns of activity and an exponential avalanche size distribution; this distribution was followed by a bimodal distribution, and finally a power-law-like distribution. The bimodal distribution was associated with a large-scale avalanche with a homogeneous spatiotemporal pattern, while the subsequent power-law distribution was associated with diverse patterns. These results suggest that the SoC emerges through a two-step process: the integration process accompanying the characteristic large-scale avalanche and the fragmentation process associated with diverse middle-size avalanches. Close http://www.sciencedirect.com/science/article/pii/S0306452216306522 doi:10.1016/j.neuroscience.2016.11.031 Close
2016
	Gong, Wei; Sencar, Jure; Bakkum, Douglas J; Jäckel, David; Obien, Marie Engelene J; Radivojevic, Milos; Hierlemann, Andreas Multiple single-unit long-term tracking on organotypic hippocampal slices using high-density microelectrode arrays Journal Article Frontiers in Neuroscience, 10 , pp. 1-16, 2016, ISSN: 1662453X. Abstract \| Links \| BibTeX \| Tags: Brain Slice, ETH-CMOS-MEA @article{Gong2016, title = {Multiple single-unit long-term tracking on organotypic hippocampal slices using high-density microelectrode arrays}, author = {Wei Gong and Jure Sencar and Douglas J Bakkum and David Jäckel and Marie Engelene J Obien and Milos Radivojevic and Andreas Hierlemann}, url = {https://www.frontiersin.org/articles/10.3389/fnins.2016.00537/full}, doi = {10.3389/fnins.2016.00537}, issn = {1662453X}, year = {2016}, date = {2016-11-22}, journal = {Frontiers in Neuroscience}, volume = {10}, pages = {1-16}, abstract = {A novel system to cultivate and record from organotypic brain slices directly on high-density microelectrode arrays (HD-MEA) was developed. This system allows for continuous recording of electrical activity of specific individual neurons at high spatial resolution while monitoring at the same time, neuronal network activity. For the first time, the electrical activity patterns of single neurons and the corresponding neuronal network in an organotypic hippocampal slice culture were studied during several consecutive weeks at daily intervals. An unsupervised iterative spike-sorting algorithm, based on PCA and k-means clustering, was developed to assign the activities to the single units. Spike-triggered average extracellular waveforms of an action potential recorded across neighboring electrodes, termed ‘footprints' of single-units were generated and tracked over weeks. The developed system offers the potential to study chronic impacts of drugs or genetic modifications on individual neurons in slice preparations over extended times.}, keywords = {Brain Slice, ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close A novel system to cultivate and record from organotypic brain slices directly on high-density microelectrode arrays (HD-MEA) was developed. This system allows for continuous recording of electrical activity of specific individual neurons at high spatial resolution while monitoring at the same time, neuronal network activity. For the first time, the electrical activity patterns of single neurons and the corresponding neuronal network in an organotypic hippocampal slice culture were studied during several consecutive weeks at daily intervals. An unsupervised iterative spike-sorting algorithm, based on PCA and k-means clustering, was developed to assign the activities to the single units. Spike-triggered average extracellular waveforms of an action potential recorded across neighboring electrodes, termed ‘footprints' of single-units were generated and tracked over weeks. The developed system offers the potential to study chronic impacts of drugs or genetic modifications on individual neurons in slice preparations over extended times. Close https://www.frontiersin.org/articles/10.3389/fnins.2016.00537/full doi:10.3389/fnins.2016.00537 Close
	Deligkaris, Kosmas; Bullmann, Torsten; Frey, Urs Extracellularly Recorded Somatic and Neuritic Signal Shapes and Classification Algorithms for High-Density Microelectrode Array Electrophysiology Journal Article Frontiers in Neuroscience, 10 , pp. 421, 2016, ISSN: 1662-453X. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks @article{Frey2016, title = {Extracellularly Recorded Somatic and Neuritic Signal Shapes and Classification Algorithms for High-Density Microelectrode Array Electrophysiology}, author = {Kosmas Deligkaris and Torsten Bullmann and Urs Frey}, url = {https://www.frontiersin.org/article/10.3389/fnins.2016.00421}, doi = {10.3389/fnins.2016.00421}, issn = {1662-453X}, year = {2016}, date = {2016-09-14}, journal = {Frontiers in Neuroscience}, volume = {10}, pages = {421}, abstract = {High-density microelectrode arrays (HDMEA) have been recently introduced to study principles of neural function at high spatial resolution. However, the exact nature of the experimentally observed extracellular action potentials (EAPs) is still incompletely understood. The soma, axon and dendrites of a neuron can all exhibit regenerative action potentials that could be sensed with HDMEA electrodes. Here, we investigate the contribution of distinct neuronal sources of activity in HDMEA recordings from low-density neuronal cultures. We recorded EAPs with HDMEAs having 11,011 electrodes and then fixed and immunostained the cultures with beta3-tubulin for high-resolution fluorescence imaging. Immunofluorescence images overlaid with the activity maps showed EAPs both at neuronal somata and distal neurites. Neuritic EAPs had mostly narrow triphasic shapes, consisting of a positive, a pronounced negative peak and a second positive peak. EAPs near somata had wide monophasic or biphasic shapes with a main negative peak, and following optional positive peak. We show that about 86% of EAP recordings consist of somatic spikes, while the remaining 14% represent neuritic spikes. Furthermore, the adaptation of the waveform shape during bursts of these neuritic spikes suggested that they originate from axons, rather than from dendrites. Our study improves the understanding of HDMEA signals and can aid in the identification of the source of EAPs.}, keywords = {ETH-CMOS-MEA, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close High-density microelectrode arrays (HDMEA) have been recently introduced to study principles of neural function at high spatial resolution. However, the exact nature of the experimentally observed extracellular action potentials (EAPs) is still incompletely understood. The soma, axon and dendrites of a neuron can all exhibit regenerative action potentials that could be sensed with HDMEA electrodes. Here, we investigate the contribution of distinct neuronal sources of activity in HDMEA recordings from low-density neuronal cultures. We recorded EAPs with HDMEAs having 11,011 electrodes and then fixed and immunostained the cultures with beta3-tubulin for high-resolution fluorescence imaging. Immunofluorescence images overlaid with the activity maps showed EAPs both at neuronal somata and distal neurites. Neuritic EAPs had mostly narrow triphasic shapes, consisting of a positive, a pronounced negative peak and a second positive peak. EAPs near somata had wide monophasic or biphasic shapes with a main negative peak, and following optional positive peak. We show that about 86% of EAP recordings consist of somatic spikes, while the remaining 14% represent neuritic spikes. Furthermore, the adaptation of the waveform shape during bursts of these neuritic spikes suggested that they originate from axons, rather than from dendrites. Our study improves the understanding of HDMEA signals and can aid in the identification of the source of EAPs. Close https://www.frontiersin.org/article/10.3389/fnins.2016.00421 doi:10.3389/fnins.2016.00421 Close
	Radivojevic, Milos; Jäckel, David; Altermatt, Michael; Müller, Jan; Viswam, Vijay; Hierlemann, Andreas; Bakkum, Douglas J Electrical Identification and Selective Microstimulation of Neuronal Compartments Based on Features of Extracellular Action Potentials Journal Article Scientific Reports, 6 (1), pp. 1-20, 2016, ISSN: 2045-2322. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks, Stimulation @article{Radivojevic2016, title = {Electrical Identification and Selective Microstimulation of Neuronal Compartments Based on Features of Extracellular Action Potentials}, author = {Milos Radivojevic and David Jäckel and Michael Altermatt and Jan Müller and Vijay Viswam and Andreas Hierlemann and Douglas J Bakkum}, url = {http://www.nature.com/articles/srep31332}, doi = {10.1038/srep31332}, issn = {2045-2322}, year = {2016}, date = {2016-08-11}, journal = {Scientific Reports}, volume = {6}, number = {1}, pages = {1-20}, abstract = {A detailed, high-spatiotemporal-resolution characterization of neuronal responses to local electrical fields and the capability of precise extracellular microstimulation of selected neurons are pivotal for studying and manipulating neuronal activity and circuits in networks and for developing neural prosthetics. Here, we studied cultured neocortical neurons by using high-density microelectrode arrays and optical imaging, complemented by the patch-clamp technique, and with the aim to correlate morphological and electrical features of neuronal compartments with their responsiveness to extracellular stimulation. We developed strategies to electrically identify any neuron in the network, while subcellular spatial resolution recording of extracellular action potential (AP) traces enabled their assignment to the axon initial segment (AIS), axonal arbor and proximal somatodendritic compartments. Stimulation at the AIS required low voltages and provided immediate, selective and reliable neuronal activation, whereas stimulation at the soma required high voltages and produced delayed and unreliable responses. Subthreshold stimulation at the soma depolarized the somatic membrane potential without eliciting APs.}, keywords = {ETH-CMOS-MEA, Neuronal Networks, Stimulation}, pubstate = {published}, tppubtype = {article} } Close A detailed, high-spatiotemporal-resolution characterization of neuronal responses to local electrical fields and the capability of precise extracellular microstimulation of selected neurons are pivotal for studying and manipulating neuronal activity and circuits in networks and for developing neural prosthetics. Here, we studied cultured neocortical neurons by using high-density microelectrode arrays and optical imaging, complemented by the patch-clamp technique, and with the aim to correlate morphological and electrical features of neuronal compartments with their responsiveness to extracellular stimulation. We developed strategies to electrically identify any neuron in the network, while subcellular spatial resolution recording of extracellular action potential (AP) traces enabled their assignment to the axon initial segment (AIS), axonal arbor and proximal somatodendritic compartments. Stimulation at the AIS required low voltages and provided immediate, selective and reliable neuronal activation, whereas stimulation at the soma required high voltages and produced delayed and unreliable responses. Subthreshold stimulation at the soma depolarized the somatic membrane potential without eliciting APs. Close http://www.nature.com/articles/srep31332 doi:10.1038/srep31332 Close
	Franke, Felix; Fiscella, Michele; Sevelev, Maksim; Roska, Botond; Hierlemann, Andreas; Azeredo da Silveira, Rava Structures of Neural Correlation and How They Favor Coding Journal Article Neuron, 89 (2), pp. 409-422, 2016, ISSN: 10974199. Abstract \| Links \| BibTeX \| Tags: Data Analysis, ETH-CMOS-MEA, Neuronal Networks, Retina @article{Franke2016, title = {Structures of Neural Correlation and How They Favor Coding}, author = {Felix Franke and Michele Fiscella and Maksim Sevelev and Botond Roska and Andreas Hierlemann and Rava {Azeredo da Silveira}}, url = {http://www.sciencedirect.com/science/article/pii/S0896627315011393?via%3Dihub}, doi = {10.1016/j.neuron.2015.12.037}, issn = {10974199}, year = {2016}, date = {2016-01-20}, journal = {Neuron}, volume = {89}, number = {2}, pages = {409-422}, publisher = {Elsevier Inc.}, abstract = {The neural representation of information suffers from "noise"-the trial-to-trial variability in the response of neurons. The impact of correlated noise upon population coding has been debated, but a direct connection between theory and experiment remains tenuous. Here, we substantiate this connection and propose a refined theoretical picture. Using simultaneous recordings from a population of direction-selective retinal ganglion cells, we demonstrate that coding benefits from noise correlations. The effect is appreciable already in small populations, yet it is a collective phenomenon. Furthermore, the stimulus-dependent structure of correlation is key. We develop simple functional models that capture the stimulus-dependent statistics. We then use them to quantify the performance of population coding, which depends upon interplays of feature sensitivities and noise correlations in the population. Because favorable structures of correlation emerge robustly in circuits with noisy, nonlinear elements, they will arise and benefit coding beyond the confines of retina. Coding in the brain suffers from the variability of neural responses. Using experiment and theory, Franke et al. show that this "noise" comes with a particular structure, which emerges from circuit properties and which counteracts the harmful effect of variability.}, keywords = {Data Analysis, ETH-CMOS-MEA, Neuronal Networks, Retina}, pubstate = {published}, tppubtype = {article} } Close The neural representation of information suffers from "noise"-the trial-to-trial variability in the response of neurons. The impact of correlated noise upon population coding has been debated, but a direct connection between theory and experiment remains tenuous. Here, we substantiate this connection and propose a refined theoretical picture. Using simultaneous recordings from a population of direction-selective retinal ganglion cells, we demonstrate that coding benefits from noise correlations. The effect is appreciable already in small populations, yet it is a collective phenomenon. Furthermore, the stimulus-dependent structure of correlation is key. We develop simple functional models that capture the stimulus-dependent statistics. We then use them to quantify the performance of population coding, which depends upon interplays of feature sensitivities and noise correlations in the population. Because favorable structures of correlation emerge robustly in circuits with noisy, nonlinear elements, they will arise and benefit coding beyond the confines of retina. Coding in the brain suffers from the variability of neural responses. Using experiment and theory, Franke et al. show that this "noise" comes with a particular structure, which emerges from circuit properties and which counteracts the harmful effect of variability. Close http://www.sciencedirect.com/science/article/pii/S0896627315011393?via%3Dihub doi:10.1016/j.neuron.2015.12.037 Close
	Yonehara, Keisuke; Fiscella, Michele; Drinnenberg, Antonia; Esposti, Federico; Trenholm, Stuart; Krol, Jacek; Franke, Felix; Scherf, Brigitte Gross; Kusnyerik, Akos; Müller, Jan; Szabo, Arnold; Jüttner, Josephine; Cordoba, Francisco; Reddy, Ashrithpal Police; Németh, János; Nagy, Zoltán Zsolt; Munier, Francis; Hierlemann, Andreas; Roska, Botond Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity Journal Article Neuron, 89 (1), pp. 177-193, 2016, ISSN: 10974199. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Retina @article{Yonehara2016, title = {Congenital Nystagmus Gene FRMD7 Is Necessary for Establishing a Neuronal Circuit Asymmetry for Direction Selectivity}, author = {Keisuke Yonehara and Michele Fiscella and Antonia Drinnenberg and Federico Esposti and Stuart Trenholm and Jacek Krol and Felix Franke and Brigitte Gross Scherf and Akos Kusnyerik and Jan Müller and Arnold Szabo and Josephine Jüttner and Francisco Cordoba and Ashrithpal Police Reddy and János Németh and Zoltán Zsolt Nagy and Francis Munier and Andreas Hierlemann and Botond Roska}, url = {http://www.sciencedirect.com/science/article/pii/S0896627315010387?via%3Dihub}, doi = {10.1016/j.neuron.2015.11.032}, issn = {10974199}, year = {2016}, date = {2016-01-06}, journal = {Neuron}, volume = {89}, number = {1}, pages = {177-193}, abstract = {Neuronal circuit asymmetries are important components of brain circuits, but the molecular pathways leading to their establishment remain unknown. Here we found that the mutation of FRMD7, a gene that is defective in human congenital nystagmus, leads to the selective loss of the horizontal optokinetic reflex in mice, as it does in humans. This is accompanied by the selective loss of horizontal direction selectivity in retinal ganglion cells and the transition from asymmetric to symmetric inhibitory input to horizontal direction-selective ganglion cells. In wild-type retinas, we found FRMD7 specifically expressed in starburst amacrine cells, the interneuron type that provides asymmetric inhibition to direction-selective retinal ganglion cells. This work identifies FRMD7 as a key regulator in establishing a neuronal circuit asymmetry, and it suggests the involvement of a specific inhibitory neuron type in the pathophysiology of a neurological disease.}, keywords = {ETH-CMOS-MEA, Retina}, pubstate = {published}, tppubtype = {article} } Close Neuronal circuit asymmetries are important components of brain circuits, but the molecular pathways leading to their establishment remain unknown. Here we found that the mutation of FRMD7, a gene that is defective in human congenital nystagmus, leads to the selective loss of the horizontal optokinetic reflex in mice, as it does in humans. This is accompanied by the selective loss of horizontal direction selectivity in retinal ganglion cells and the transition from asymmetric to symmetric inhibitory input to horizontal direction-selective ganglion cells. In wild-type retinas, we found FRMD7 specifically expressed in starburst amacrine cells, the interneuron type that provides asymmetric inhibition to direction-selective retinal ganglion cells. This work identifies FRMD7 as a key regulator in establishing a neuronal circuit asymmetry, and it suggests the involvement of a specific inhibitory neuron type in the pathophysiology of a neurological disease. Close http://www.sciencedirect.com/science/article/pii/S0896627315010387?via%3Dihub doi:10.1016/j.neuron.2015.11.032 Close
2015
	Jones, Ian L; Russell, Thomas L; Farrow, Karl; Fiscella, Michele; Franke, Felix; Müller, Jan; Jäckel, David; Hierlemann, Andreas A method for electrophysiological characterization of hamster retinal ganglion cells using a high-density CMOS microelectrode array Journal Article Frontiers in Neuroscience, 9 , pp. 360, 2015, ISSN: 1662453X. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Retina @article{Jones2015, title = {A method for electrophysiological characterization of hamster retinal ganglion cells using a high-density CMOS microelectrode array}, author = {Ian L Jones and Thomas L Russell and Karl Farrow and Michele Fiscella and Felix Franke and Jan Müller and David Jäckel and Andreas Hierlemann}, url = {https://www.frontiersin.org/articles/10.3389/fnins.2015.00360/full}, doi = {10.3389/fnins.2015.00360}, issn = {1662453X}, year = {2015}, date = {2015-10-13}, journal = {Frontiers in Neuroscience}, volume = {9}, pages = {360}, abstract = {Knowledge of neuronal cell types in the mammalian retina is important for the understanding of human retinal disease and the advancement of sight-restoring technology, such as retinal prosthetic devices. A somewhat less utilized animal model for retinal research is the hamster, which has a visual system that is characterized by an area centralis and a wide visual field with a broad binocular component. The hamster retina is optimally suited for recording on the microelectrode array (MEA), because it intrinsically lies flat on the MEA surface and yields robust, large-amplitude signals. However, information in the literature about hamster retinal ganglion cell functional types is scarce. The goal of our work is to develop a method featuring a high-density (HD) Complementary metal-oxide-semiconductor (CMOS) MEA technology along with a sequence of standardized visual stimuli in order to categorize ganglion cells in isolated Syrian Hamster (Mesocricetus auratus) retina. Since the HD-MEA is capable of recording at a higher spatial resolution than most MEA systems (17.5 um electrode pitch), we capitalized on this feature and were able to record from a large proportion of RGCs within a selected region. Secondly, we chose our stimuli so that they could be run during the experiment without intervention or computation steps. The visual stimulus set was designed to activate the receptive fields of most ganglion cells in parallel and to incorporate various visual features to which different cell types respond uniquely. Based on the ganglion cell responses, basic cell properties were determined: direction selectivity, speed tuning, width tuning, transience and latency. These properties were clustered in order to identify ganglion cell types in the hamster retina. Ultimately, we recorded up to a cell density 2780 cells/mm2 at 2 mm (42°) from the optic nerve head. Using 5 parameters extracted from the responses to visual stimuli, we obtained 7 ganglion cell types.}, keywords = {ETH-CMOS-MEA, Retina}, pubstate = {published}, tppubtype = {article} } Close Knowledge of neuronal cell types in the mammalian retina is important for the understanding of human retinal disease and the advancement of sight-restoring technology, such as retinal prosthetic devices. A somewhat less utilized animal model for retinal research is the hamster, which has a visual system that is characterized by an area centralis and a wide visual field with a broad binocular component. The hamster retina is optimally suited for recording on the microelectrode array (MEA), because it intrinsically lies flat on the MEA surface and yields robust, large-amplitude signals. However, information in the literature about hamster retinal ganglion cell functional types is scarce. The goal of our work is to develop a method featuring a high-density (HD) Complementary metal-oxide-semiconductor (CMOS) MEA technology along with a sequence of standardized visual stimuli in order to categorize ganglion cells in isolated Syrian Hamster (Mesocricetus auratus) retina. Since the HD-MEA is capable of recording at a higher spatial resolution than most MEA systems (17.5 um electrode pitch), we capitalized on this feature and were able to record from a large proportion of RGCs within a selected region. Secondly, we chose our stimuli so that they could be run during the experiment without intervention or computation steps. The visual stimulus set was designed to activate the receptive fields of most ganglion cells in parallel and to incorporate various visual features to which different cell types respond uniquely. Based on the ganglion cell responses, basic cell properties were determined: direction selectivity, speed tuning, width tuning, transience and latency. These properties were clustered in order to identify ganglion cell types in the hamster retina. Ultimately, we recorded up to a cell density 2780 cells/mm2 at 2 mm (42°) from the optic nerve head. Using 5 parameters extracted from the responses to visual stimuli, we obtained 7 ganglion cell types. Close https://www.frontiersin.org/articles/10.3389/fnins.2015.00360/full doi:10.3389/fnins.2015.00360 Close
	Fiscella, Michele; Franke, Felix; Farrow, Karl; Müller, Jan; Roska, Botond; Azeredo da Silveira, Rava ; Hierlemann, Andreas Visual coding with a population of direction-selective neurons Journal Article Journal of Neurophysiology, 114 (4), pp. 2485-2499, 2015, ISSN: 0022-3077. Abstract \| Links \| BibTeX \| Tags: Data Analysis, ETH-CMOS-MEA, Retina @article{Fiscella2015, title = {Visual coding with a population of direction-selective neurons}, author = {Michele Fiscella and Felix Franke and Karl Farrow and Jan Müller and Botond Roska and Rava {Azeredo da Silveira} and Andreas Hierlemann}, url = {http://jn.physiology.org/lookup/doi/10.1152/jn.00919.2014}, doi = {10.1152/jn.00919.2014}, issn = {0022-3077}, year = {2015}, date = {2015-08-19}, journal = {Journal of Neurophysiology}, volume = {114}, number = {4}, pages = {2485-2499}, abstract = {The brain decodes the visual scene from the action potentials of ∼20 retinal ganglion cell types. Among the retinal ganglion cells, direction-selective ganglion cells (DSGCs) encode motion direction. Several studies have focused on the encoding or decoding of motion direction by recording multiunit activity, mainly in the visual cortex. In this study, we simultaneously recorded from all four types of ON-OFF DSGCs of the rabbit retina using a microelectronics-based high-density microelectrode array (HDMEA) and decoded their concerted activity using probabilistic and linear decoders. Furthermore, we investigated how the modification of stimulus parameters (velocity, size, angle of moving object) and the use of different tuning curve fits influenced decoding precision. Finally, we simulated ON-OFF DSGC activity, based on real data, in order to understand how tuning curve widths and the angular distribution of the cells' preferred directions influence decoding performance. We found that probabilistic decoding strategies outperformed, on average, linear methods and that decoding precision was robust to changes in stimulus parameters such as velocity. The removal of noise correlations among cells, by random shuffling trials, caused a drop in decoding precision. Moreover, we found that tuning curves are broad in order to minimize large errors at the expense of a higher average error, and that the retinal direction-selective system would not substantially benefit, on average, from having more than four types of ON-OFF DSGCs or from a perfect alignment of the cells' preferred directions.}, keywords = {Data Analysis, ETH-CMOS-MEA, Retina}, pubstate = {published}, tppubtype = {article} } Close The brain decodes the visual scene from the action potentials of ∼20 retinal ganglion cell types. Among the retinal ganglion cells, direction-selective ganglion cells (DSGCs) encode motion direction. Several studies have focused on the encoding or decoding of motion direction by recording multiunit activity, mainly in the visual cortex. In this study, we simultaneously recorded from all four types of ON-OFF DSGCs of the rabbit retina using a microelectronics-based high-density microelectrode array (HDMEA) and decoded their concerted activity using probabilistic and linear decoders. Furthermore, we investigated how the modification of stimulus parameters (velocity, size, angle of moving object) and the use of different tuning curve fits influenced decoding precision. Finally, we simulated ON-OFF DSGC activity, based on real data, in order to understand how tuning curve widths and the angular distribution of the cells' preferred directions influence decoding performance. We found that probabilistic decoding strategies outperformed, on average, linear methods and that decoding precision was robust to changes in stimulus parameters such as velocity. The removal of noise correlations among cells, by random shuffling trials, caused a drop in decoding precision. Moreover, we found that tuning curves are broad in order to minimize large errors at the expense of a higher average error, and that the retinal direction-selective system would not substantially benefit, on average, from having more than four types of ON-OFF DSGCs or from a perfect alignment of the cells' preferred directions. Close http://jn.physiology.org/lookup/doi/10.1152/jn.00919.2014 doi:10.1152/jn.00919.2014 Close
	Okawa, Satoru; Mita, Takeshi; Bakkum, Douglas J; Frey, Urs; Hierlemann, Andreas; Kanzaki, Ryohei; Takahashi, Hirokazu Chronic Co-Variation of Neural Network Configuration and Activity in Mature Dissociated Cultures Journal Article Electronics and Communications in Japan, 98 (5), pp. 34-42, 2015, ISSN: 1942-9541. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks @article{Takahashi2015, title = {Chronic Co-Variation of Neural Network Configuration and Activity in Mature Dissociated Cultures}, author = {Satoru Okawa and Takeshi Mita and Douglas J Bakkum and Urs Frey and Andreas Hierlemann and Ryohei Kanzaki and Hirokazu Takahashi}, url = {http://onlinelibrary.wiley.com/doi/10.1002/ecj.11736/abstract;jsessionid=791557FA80CF36B1F78DC538C1618924.f03t02}, doi = {10.1002/ecj.11736}, issn = {1942-9541}, year = {2015}, date = {2015-04-08}, journal = {Electronics and Communications in Japan}, volume = {98}, number = {5}, pages = {34-42}, abstract = {Spatiotemporal neural patterns depend on the physical structure of neural circuits. Neural plasticity can thus be associated with changes in the circuit structure. For example, newborn neurons migrate toward existing, already matured, neural networks in order to participate in neural computation. In the present study, we have conducted two experiments to investigate how neural migration is associated with the development of neural activity in primary dissociated cultures of neuronal cells. In Experiment 1, using a mature culture, a high-density CMOS microelectrode array was used to continuously monitor neural migration and activity for more than two weeks. Consequently, we found that even in mature neuronal cultures neurons moved 2.0 ± 1.0 mum a day and that the moving distance was negatively correlated with their firing rate, suggesting that neurons featuring low firing rates tend to migrate actively. In Experiment 2 using a co-culture of mature and immature neurons, we found that immature neurons moved more actively than matured neurons to achieve functional connections to other neurons. These findings suggest that neurons with low firing rates as well as newborn neurons actively migrate in order to establish their connections and function in a neuronal network.}, keywords = {ETH-CMOS-MEA, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close Spatiotemporal neural patterns depend on the physical structure of neural circuits. Neural plasticity can thus be associated with changes in the circuit structure. For example, newborn neurons migrate toward existing, already matured, neural networks in order to participate in neural computation. In the present study, we have conducted two experiments to investigate how neural migration is associated with the development of neural activity in primary dissociated cultures of neuronal cells. In Experiment 1, using a mature culture, a high-density CMOS microelectrode array was used to continuously monitor neural migration and activity for more than two weeks. Consequently, we found that even in mature neuronal cultures neurons moved 2.0 ± 1.0 mum a day and that the moving distance was negatively correlated with their firing rate, suggesting that neurons featuring low firing rates tend to migrate actively. In Experiment 2 using a co-culture of mature and immature neurons, we found that immature neurons moved more actively than matured neurons to achieve functional connections to other neurons. These findings suggest that neurons with low firing rates as well as newborn neurons actively migrate in order to establish their connections and function in a neuronal network. Close http://onlinelibrary.wiley.com/doi/10.1002/ecj.11736/abstract;jsessionid=791557F[...] doi:10.1002/ecj.11736 Close
	Lewandowska, Marta K; Bakkum, Douglas J; Rompani, Santiago B; Hierlemann, Andreas Recording large extracellular spikes in microchannels along many axonal sites from individual neurons Journal Article PLoS ONE, 10 (3), pp. 1-24, 2015, ISSN: 19326203. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Neuronal Networks @article{Lewandowska2015, title = {Recording large extracellular spikes in microchannels along many axonal sites from individual neurons}, author = {Marta K Lewandowska and Douglas J Bakkum and Santiago B Rompani and Andreas Hierlemann}, url = {http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118514}, doi = {10.1371/journal.pone.0118514}, issn = {19326203}, year = {2015}, date = {2015-03-03}, journal = {PLoS ONE}, volume = {10}, number = {3}, pages = {1-24}, abstract = {The numerous connections between neuronal cell bodies, made by their dendrites and axons, are vital for information processing in the brain. While dendrites and synapses have been extensively studied, axons have remained elusive to a large extent. We present a novel platform to study axonal physiology and information processing based on combining an 11,011-electrode high-density complementary metal-oxide semiconductor microelectrode array with a poly(dimethylsiloxane) channel device, which isolates axons from somas and, importantly, significantly amplifies recorded axonal signals. The combination of the microelectrode array with recording and stimulation capability with the microfluidic isolation channels permitted us to study axonal signal behavior at great detail. The device, featuring two culture chambers with over 30 channels spanning in between, enabled long-term recording of single spikes from isolated axons with signal amplitudes of 100 uV up to 2 mV. Propagating signals along axons could be recorded with 10 to 50 electrodes per channel. We (i) describe the performance and capabilities of our device for axonal electrophysiology, and (ii) present novel data on axonal signals facilitated by the device. Spontaneous action potentials with characteristic shapes propagated from somas along axons between the two compartments, and these unique shapes could be used to identify individual axons within channels that contained many axonal branches. Stimulation through the electrode array facilitated the identification of somas and their respective axons, enabling interfacing with different compartments of a single cell. Complex spike shapes observed in channels were traced back to single cells, and we show that more complicated spike shapes originate from a linear superposition of multiple axonal signals rather than signal distortion by the channels.}, keywords = {ETH-CMOS-MEA, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close The numerous connections between neuronal cell bodies, made by their dendrites and axons, are vital for information processing in the brain. While dendrites and synapses have been extensively studied, axons have remained elusive to a large extent. We present a novel platform to study axonal physiology and information processing based on combining an 11,011-electrode high-density complementary metal-oxide semiconductor microelectrode array with a poly(dimethylsiloxane) channel device, which isolates axons from somas and, importantly, significantly amplifies recorded axonal signals. The combination of the microelectrode array with recording and stimulation capability with the microfluidic isolation channels permitted us to study axonal signal behavior at great detail. The device, featuring two culture chambers with over 30 channels spanning in between, enabled long-term recording of single spikes from isolated axons with signal amplitudes of 100 uV up to 2 mV. Propagating signals along axons could be recorded with 10 to 50 electrodes per channel. We (i) describe the performance and capabilities of our device for axonal electrophysiology, and (ii) present novel data on axonal signals facilitated by the device. Spontaneous action potentials with characteristic shapes propagated from somas along axons between the two compartments, and these unique shapes could be used to identify individual axons within channels that contained many axonal branches. Stimulation through the electrode array facilitated the identification of somas and their respective axons, enabling interfacing with different compartments of a single cell. Complex spike shapes observed in channels were traced back to single cells, and we show that more complicated spike shapes originate from a linear superposition of multiple axonal signals rather than signal distortion by the channels. Close http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118514 doi:10.1371/journal.pone.0118514 Close
2014
	Bakkum, Douglas J; Radivojevic, Milos; Frey, Urs; Franke, Felix; Hierlemann, Andreas; Takahashi, Hirokazu Parameters for burst detection Journal Article Frontiers in Computational Neuroscience, 7 , pp. 1-12, 2014, ISSN: 1662-5188. Abstract \| Links \| BibTeX \| Tags: Data Analysis, ETH-CMOS-MEA @article{Bakkum2014, title = {Parameters for burst detection}, author = {Douglas J Bakkum and Milos Radivojevic and Urs Frey and Felix Franke and Andreas Hierlemann and Hirokazu Takahashi}, url = {http://journal.frontiersin.org/article/10.3389/fncom.2013.00193/abstract}, doi = {10.3389/fncom.2013.00193}, issn = {1662-5188}, year = {2014}, date = {2014-01-13}, journal = {Frontiers in Computational Neuroscience}, volume = {7}, pages = {1-12}, abstract = {Bursts of action potentials within neurons and throughout networks are believed to serve roles in how neurons handle and store information, both in vivo and in vitro. Accurate detection of burst occurrences and durations are therefore crucial for many studies. A number of algorithms have been proposed to do so, but a standard method has not been adopted. This is due, in part, to many algorithms requiring the adjustment of multiple ad-hoc parameters and further post-hoc criteria in order to produce satisfactory results. Here, we broadly catalog existing approaches and present a new approach requiring the selection of only a single parameter: the number of spikes N comprising the smallest burst to consider. A burst was identified if N spikes occurred in less than T ms, where the threshold T was automatically determined from observing a probability distribution of inter-spike-intervals. Performance was compared vs. different classes of detectors on data gathered from in vitro neuronal networks grown over microelectrode arrays. Our approach offered a number of useful features including: a simple implementation, no need for ad-hoc or post-hoc criteria, and precise assignment of burst boundary time points. Unlike existing approaches, detection was not biased toward larger bursts, allowing identification and analysis of a greater range of neuronal and network dynamics.}, keywords = {Data Analysis, ETH-CMOS-MEA}, pubstate = {published}, tppubtype = {article} } Close Bursts of action potentials within neurons and throughout networks are believed to serve roles in how neurons handle and store information, both in vivo and in vitro. Accurate detection of burst occurrences and durations are therefore crucial for many studies. A number of algorithms have been proposed to do so, but a standard method has not been adopted. This is due, in part, to many algorithms requiring the adjustment of multiple ad-hoc parameters and further post-hoc criteria in order to produce satisfactory results. Here, we broadly catalog existing approaches and present a new approach requiring the selection of only a single parameter: the number of spikes N comprising the smallest burst to consider. A burst was identified if N spikes occurred in less than T ms, where the threshold T was automatically determined from observing a probability distribution of inter-spike-intervals. Performance was compared vs. different classes of detectors on data gathered from in vitro neuronal networks grown over microelectrode arrays. Our approach offered a number of useful features including: a simple implementation, no need for ad-hoc or post-hoc criteria, and precise assignment of burst boundary time points. Unlike existing approaches, detection was not biased toward larger bursts, allowing identification and analysis of a greater range of neuronal and network dynamics. Close http://journal.frontiersin.org/article/10.3389/fncom.2013.00193/abstract doi:10.3389/fncom.2013.00193 Close
2013
	Bakkum, Douglas J; Frey, Urs; Radivojevic, Milos; Russell, Thomas L; Müller, Jan; Fiscella, Michele; Takahashi, Hirokazu; Hierlemann, Andreas Tracking axonal action potential propagation on a high-density microelectrode array across hundreds of sites Journal Article Nature Communications, 4 , pp. 1-12, 2013, ISSN: 2041-1723. Abstract \| Links \| BibTeX \| Tags: Data Analysis, ETH-CMOS-MEA, Neuronal Networks @article{Bakkum2013, title = {Tracking axonal action potential propagation on a high-density microelectrode array across hundreds of sites}, author = {Douglas J Bakkum and Urs Frey and Milos Radivojevic and Thomas L Russell and Jan Müller and Michele Fiscella and Hirokazu Takahashi and Andreas Hierlemann}, url = {http://www.nature.com/doifinder/10.1038/ncomms3181}, doi = {10.1038/ncomms3181}, issn = {2041-1723}, year = {2013}, date = {2013-07-19}, journal = {Nature Communications}, volume = {4}, pages = {1-12}, abstract = {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.}, keywords = {Data Analysis, ETH-CMOS-MEA, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close 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. Close http://www.nature.com/doifinder/10.1038/ncomms3181 doi:10.1038/ncomms3181 Close
	Müller, Jan; Bakkum, Douglas J; Hierlemann, Andreas Sub-millisecond closed-loop feedback stimulation between arbitrary sets of individual neurons. Journal Article Frontiers in Neural Circuits, 6 , pp. 121, 2013, ISSN: 1662-5110. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MEA Technology, Neuronal Networks, Stimulation @article{Muller2012, title = {Sub-millisecond closed-loop feedback stimulation between arbitrary sets of individual neurons.}, author = {Jan Müller and Douglas J Bakkum and Andreas Hierlemann}, url = {https://www.frontiersin.org/articles/10.3389/fncir.2012.00121/full}, doi = {10.3389/fncir.2012.00121}, issn = {1662-5110}, year = {2013}, date = {2013-01-10}, journal = {Frontiers in Neural Circuits}, volume = {6}, pages = {121}, abstract = {We present a system to artificially correlate the spike timing between sets of arbitrary neurons that were interfaced to a complementary metal-oxide-semiconductor (CMOS) high-density microelectrode array (MEA). The system features a novel reprogrammable and flexible event engine unit to detect arbitrary spatio-temporal patterns of recorded action potentials and is capable of delivering sub-millisecond closed-loop feedback of electrical stimulation upon trigger events in real-time. The relative timing between action potentials of individual neurons as well as the temporal pattern among multiple neurons, or neuronal assemblies, is considered an important factor governing memory and learning in the brain. Artificially changing timings between arbitrary sets of spiking neurons with our system could provide a "knob" to tune information processing in the network.}, keywords = {ETH-CMOS-MEA, MEA Technology, Neuronal Networks, Stimulation}, pubstate = {published}, tppubtype = {article} } Close We present a system to artificially correlate the spike timing between sets of arbitrary neurons that were interfaced to a complementary metal-oxide-semiconductor (CMOS) high-density microelectrode array (MEA). The system features a novel reprogrammable and flexible event engine unit to detect arbitrary spatio-temporal patterns of recorded action potentials and is capable of delivering sub-millisecond closed-loop feedback of electrical stimulation upon trigger events in real-time. The relative timing between action potentials of individual neurons as well as the temporal pattern among multiple neurons, or neuronal assemblies, is considered an important factor governing memory and learning in the brain. Artificially changing timings between arbitrary sets of spiking neurons with our system could provide a "knob" to tune information processing in the network. Close https://www.frontiersin.org/articles/10.3389/fncir.2012.00121/full doi:10.3389/fncir.2012.00121 Close
2012
	Fiscella, Michele; Farrow, Karl; Jones, Ian L; Jäckel, David; Müller, Jan; Frey, Urs; Bakkum, Douglas J; Hantz, Péter; Roska, Botond; Hierlemann, Andreas Recording from defined populations of retinal ganglion cells using a high-density CMOS-integrated microelectrode array with real-time switchable electrode selection Journal Article Journal of Neuroscience Methods, 211 (1), pp. 103-113, 2012, ISSN: 01650270. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Retina @article{Fiscella2012, title = {Recording from defined populations of retinal ganglion cells using a high-density CMOS-integrated microelectrode array with real-time switchable electrode selection}, author = {Michele Fiscella and Karl Farrow and Ian L Jones and David Jäckel and Jan Müller and Urs Frey and Douglas J Bakkum and Péter Hantz and Botond Roska and Andreas Hierlemann}, url = {http://www.sciencedirect.com/science/article/pii/S0165027012003287?via%3Dihub}, doi = {10.1016/j.jneumeth.2012.08.017}, issn = {01650270}, year = {2012}, date = {2012-08-16}, journal = {Journal of Neuroscience Methods}, volume = {211}, number = {1}, pages = {103-113}, publisher = {Elsevier B.V.}, abstract = {In order to understand how retinal circuits encode visual scenes, the neural activity of defined populations of retinal ganglion cells (RGCs) has to be investigated. Here we report on a method for stimulating, detecting, and subsequently targeting defined populations of RGCs. The possibility to select a distinct population of RGCs for extracellular recording enables the design of experiments that can increase our understanding of how these neurons extract precise spatio-temporal features from the visual scene, and how the brain interprets retinal signals. We used light stimulation to elicit a response from physiologically distinct types of RGCs and then utilized the dynamic-configurability capabilities of a microelectronics-based high-density microelectrode array (MEA) to record their synchronous action potentials. The layout characteristics of the MEA made it possible to stimulate and record from multiple, highly overlapping RGCs simultaneously without light-induced artifacts. The high-density of electrodes and the high signal-to-noise ratio of the MEA circuitry allowed for recording of the activity of each RGC on 14 ± 7 electrodes. The spatial features of the electrical activity of each RGC greatly facilitated spike sorting. We were thus able to localize, identify and record from defined RGCs within a region of mouse retina. In addition, we stimulated and recorded from genetically modified RGCs to demonstrate the applicability of optogenetic methods, which introduces an additional feature to target a defined cell type. The developed methodologies can likewise be applied to other neuronal preparations including brain slices or cultured neurons.}, keywords = {ETH-CMOS-MEA, Retina}, pubstate = {published}, tppubtype = {article} } Close In order to understand how retinal circuits encode visual scenes, the neural activity of defined populations of retinal ganglion cells (RGCs) has to be investigated. Here we report on a method for stimulating, detecting, and subsequently targeting defined populations of RGCs. The possibility to select a distinct population of RGCs for extracellular recording enables the design of experiments that can increase our understanding of how these neurons extract precise spatio-temporal features from the visual scene, and how the brain interprets retinal signals. We used light stimulation to elicit a response from physiologically distinct types of RGCs and then utilized the dynamic-configurability capabilities of a microelectronics-based high-density microelectrode array (MEA) to record their synchronous action potentials. The layout characteristics of the MEA made it possible to stimulate and record from multiple, highly overlapping RGCs simultaneously without light-induced artifacts. The high-density of electrodes and the high signal-to-noise ratio of the MEA circuitry allowed for recording of the activity of each RGC on 14 ± 7 electrodes. The spatial features of the electrical activity of each RGC greatly facilitated spike sorting. We were thus able to localize, identify and record from defined RGCs within a region of mouse retina. In addition, we stimulated and recorded from genetically modified RGCs to demonstrate the applicability of optogenetic methods, which introduces an additional feature to target a defined cell type. The developed methodologies can likewise be applied to other neuronal preparations including brain slices or cultured neurons. Close http://www.sciencedirect.com/science/article/pii/S0165027012003287?via%3Dihub doi:10.1016/j.jneumeth.2012.08.017 Close
	Jäckel, David; Frey, Urs; Fiscella, Michele; Franke, Felix; Hierlemann, Andreas Applicability of independent component analysis on high-density microelectrode array recordings Journal Article Journal of Neurophysiology, 108 (1), pp. 334-348, 2012, ISSN: 0022-3077. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, Spike Sorting @article{Jackel2012, title = {Applicability of independent component analysis on high-density microelectrode array recordings}, author = {David Jäckel and Urs Frey and Michele Fiscella and Felix Franke and Andreas Hierlemann}, url = {http://jn.physiology.org/cgi/doi/10.1152/jn.01106.2011}, doi = {10.1152/jn.01106.2011}, issn = {0022-3077}, year = {2012}, date = {2012-04-04}, journal = {Journal of Neurophysiology}, volume = {108}, number = {1}, pages = {334-348}, abstract = {Emerging complementary metal oxide semiconductor (CMOS)-based, high-density microelectrode array (HD-MEA) devices provide high spatial resolution at subcellular level and a large number of readout channels. These devices allow for simultaneous recording of extracellular activity of a large number of neurons with every neuron being detected by multiple electrodes. To analyze the recorded signals, spiking events have to be assigned to individual neurons, a process referred to as "spike sorting." For a set of observed signals, which constitute a linear mixture of a set of source signals, independent component (IC) analysis (ICA) can be used to demix blindly the data and extract the individual source signals. This technique offers great potential to alleviate the problem of spike sorting in HD-MEA recordings, as it represents an unsupervised method to separate the neuronal sources. The separated sources or ICs then constitute estimates of single-neuron signals, and threshold detection on the ICs yields the sorted spike times. However, it is unknown to what extent extracellular neuronal recordings meet the requirements of ICA. In this paper, we evaluate the applicability of ICA to spike sorting of HD-MEA recordings. The analysis of extracellular neuronal signals, recorded at high spatiotemporal resolution, reveals that the recorded data cannot be modeled as a purely linear mixture. As a consequence, ICA fails to separate completely the neuronal signals and cannot be used as a stand-alone method for spike sorting in HD-MEA recordings. We assessed the demixing performance of ICA using simulated data sets and found that the performance strongly depends on neuronal density and spike amplitude. Furthermore, we show how postprocessing techniques can be used to overcome the most severe limitations of ICA. In combination with these postprocessing techniques, ICA represents a viable method to facilitate rapid spike sorting of multidimensional neuronal recordings.}, keywords = {ETH-CMOS-MEA, Spike Sorting}, pubstate = {published}, tppubtype = {article} } Close Emerging complementary metal oxide semiconductor (CMOS)-based, high-density microelectrode array (HD-MEA) devices provide high spatial resolution at subcellular level and a large number of readout channels. These devices allow for simultaneous recording of extracellular activity of a large number of neurons with every neuron being detected by multiple electrodes. To analyze the recorded signals, spiking events have to be assigned to individual neurons, a process referred to as "spike sorting." For a set of observed signals, which constitute a linear mixture of a set of source signals, independent component (IC) analysis (ICA) can be used to demix blindly the data and extract the individual source signals. This technique offers great potential to alleviate the problem of spike sorting in HD-MEA recordings, as it represents an unsupervised method to separate the neuronal sources. The separated sources or ICs then constitute estimates of single-neuron signals, and threshold detection on the ICs yields the sorted spike times. However, it is unknown to what extent extracellular neuronal recordings meet the requirements of ICA. In this paper, we evaluate the applicability of ICA to spike sorting of HD-MEA recordings. The analysis of extracellular neuronal signals, recorded at high spatiotemporal resolution, reveals that the recorded data cannot be modeled as a purely linear mixture. As a consequence, ICA fails to separate completely the neuronal signals and cannot be used as a stand-alone method for spike sorting in HD-MEA recordings. We assessed the demixing performance of ICA using simulated data sets and found that the performance strongly depends on neuronal density and spike amplitude. Furthermore, we show how postprocessing techniques can be used to overcome the most severe limitations of ICA. In combination with these postprocessing techniques, ICA represents a viable method to facilitate rapid spike sorting of multidimensional neuronal recordings. Close http://jn.physiology.org/cgi/doi/10.1152/jn.01106.2011 doi:10.1152/jn.01106.2011 Close
2011
	Hierlemann, Andreas; Frey, Urs; Hafizovic, Sadik; Heer, Flavio Growing cells atop microelectronic chips: Interfacing electrogenic cells in vitro with CMOS-based microelectrode arrays Journal Article Proceedings of the IEEE, 99 (2), pp. 252-284, 2011, ISSN: 00189219. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MEA Technology, Review @article{Hierlemann2011, title = {Growing cells atop microelectronic chips: Interfacing electrogenic cells in vitro with CMOS-based microelectrode arrays}, author = {Andreas Hierlemann and Urs Frey and Sadik Hafizovic and Flavio Heer}, url = {http://ieeexplore.ieee.org/document/5594982/}, doi = {10.1109/JPROC.2010.2066532}, issn = {00189219}, year = {2011}, date = {2011-02-01}, journal = {Proceedings of the IEEE}, volume = {99}, number = {2}, pages = {252-284}, abstract = {Complementary semiconductor-metal-oxide (CMOS) technology is a very powerful technology that can be more or less directly interfaced to electrogenic cells, like heart or brain cells in vitro. To this end, the cells are cultured directly atop the CMOS chips, which usually undergo dedicated postprocessing to obtain a reliable bidirectional interface via noble-metal microelectrodes or high-k dielectrics. The big advantages of using CMOS integrated circuits (ICs) include connectivity, the possibility to address a large number of microelectrodes on a tiny chip, and signal quality, the possibility to condition small signals right at the spot of their generation. CMOS will be demonstrated to constitute an enabling technology that opens a route to high-spatio-temporal-resolution and low-noise electrophysiological recordings from a variety of biological preparations, such as brain slices, or cultured cardiac and brain cells. The recording technique is extracellular and noninvasive, and the CMOS chips do not leak out any toxic compounds, so that the cells remain viable for extended times. In turn, the CMOS chips have been demonstrated to survive several months of culturing while being fully immersed in saline solution and being exposed to cellular metabolic products. The latter requires dedicated passivation and packaging techniques as will be shown. Fully integrated, monolithic microelectrode systems, which feature large numbers of tightly spaced microelectrodes and the associated circuitry units for bidirectional interaction (stimulation and recording), will be in the focus of this review. The respective dense microelectrode arrays (MEAs) with small pixels enable subcellular-resolution investigation of regions of interest in, e.g., neurobiological preparations, and, at the same time, the large number of electrodes allows for studying the activity of entire neuronal networks . Application areas include neuroscience, as the devices enable fundamental neurophysiological insights at the cellular and circuit level, as well as medical diagnostics and pharmacology.}, keywords = {ETH-CMOS-MEA, MEA Technology, Review}, pubstate = {published}, tppubtype = {article} } Close Complementary semiconductor-metal-oxide (CMOS) technology is a very powerful technology that can be more or less directly interfaced to electrogenic cells, like heart or brain cells in vitro. To this end, the cells are cultured directly atop the CMOS chips, which usually undergo dedicated postprocessing to obtain a reliable bidirectional interface via noble-metal microelectrodes or high-k dielectrics. The big advantages of using CMOS integrated circuits (ICs) include connectivity, the possibility to address a large number of microelectrodes on a tiny chip, and signal quality, the possibility to condition small signals right at the spot of their generation. CMOS will be demonstrated to constitute an enabling technology that opens a route to high-spatio-temporal-resolution and low-noise electrophysiological recordings from a variety of biological preparations, such as brain slices, or cultured cardiac and brain cells. The recording technique is extracellular and noninvasive, and the CMOS chips do not leak out any toxic compounds, so that the cells remain viable for extended times. In turn, the CMOS chips have been demonstrated to survive several months of culturing while being fully immersed in saline solution and being exposed to cellular metabolic products. The latter requires dedicated passivation and packaging techniques as will be shown. Fully integrated, monolithic microelectrode systems, which feature large numbers of tightly spaced microelectrodes and the associated circuitry units for bidirectional interaction (stimulation and recording), will be in the focus of this review. The respective dense microelectrode arrays (MEAs) with small pixels enable subcellular-resolution investigation of regions of interest in, e.g., neurobiological preparations, and, at the same time, the large number of electrodes allows for studying the activity of entire neuronal networks . Application areas include neuroscience, as the devices enable fundamental neurophysiological insights at the cellular and circuit level, as well as medical diagnostics and pharmacology. Close http://ieeexplore.ieee.org/document/5594982/ doi:10.1109/JPROC.2010.2066532 Close
2010
	Livi, Paolo; Heer, Flavio; Frey, Urs; Bakkum, Douglas J; Hierlemann, Andreas Compact voltage and current stimulation buffer for high-density microelectrode arrays Journal Article IEEE Transactions on Biomedical Circuits and Systems, 4 (6), pp. 372-378, 2010, ISSN: 19324545. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MEA Technology, Stimulation @article{Livi2010, title = {Compact voltage and current stimulation buffer for high-density microelectrode arrays}, author = {Paolo Livi and Flavio Heer and Urs Frey and Douglas J Bakkum and Andreas Hierlemann}, url = {http://ieeexplore.ieee.org/document/5617318/}, doi = {10.1109/TBCAS.2010.2080676}, issn = {19324545}, year = {2010}, date = {2010-11-01}, journal = {IEEE Transactions on Biomedical Circuits and Systems}, volume = {4}, number = {6}, pages = {372-378}, abstract = {We report on a compact (0.02 mm2 ) buffer for both voltage and current stimulation of electrogenic cells on a complementary metal-oxide semiconductor microelectrode array. In voltage mode, the circuit is a high-current class-AB voltage follower, based on a local common-mode feedback (LCMFB) amplifier. In current mode, the circuit is a current conveyor of type II, using the same LCMFB amplifier with cascode stages to increase the gain. The circuit shows good linearity in the 0.5-3.5 V input range and has extensively been used for stimulation of neuronal cultures.}, keywords = {ETH-CMOS-MEA, MEA Technology, Stimulation}, pubstate = {published}, tppubtype = {article} } Close We report on a compact (0.02 mm2 ) buffer for both voltage and current stimulation of electrogenic cells on a complementary metal-oxide semiconductor microelectrode array. In voltage mode, the circuit is a high-current class-AB voltage follower, based on a local common-mode feedback (LCMFB) amplifier. In current mode, the circuit is a current conveyor of type II, using the same LCMFB amplifier with cascode stages to increase the gain. The circuit shows good linearity in the 0.5-3.5 V input range and has extensively been used for stimulation of neuronal cultures. Close http://ieeexplore.ieee.org/document/5617318/ doi:10.1109/TBCAS.2010.2080676 Close
	Frey, Urs; Sedivy, Jan; Heer, Flavio; Pedron, Rene; Ballini, Marco; Müller, Jan; Bakkum, Douglas J; Hafizovic, Sadik; Faraci, Francesca D; Greve, Frauke; Kirstein, Kay Uwe; Hierlemann, Andreas Switch-matrix-based high-density microelectrode array in CMOS technology Journal Article IEEE Journal of Solid-State Circuits, 45 (2), pp. 467-482, 2010, ISSN: 00189200. Abstract \| Links \| BibTeX \| Tags: ETH-CMOS-MEA, MEA Technology @article{Frey2010, title = {Switch-matrix-based high-density microelectrode array in CMOS technology}, author = {Urs Frey and Jan Sedivy and Flavio Heer and Rene Pedron and Marco Ballini and Jan Müller and Douglas J Bakkum and Sadik Hafizovic and Francesca D Faraci and Frauke Greve and Kay Uwe Kirstein and Andreas Hierlemann}, url = {http://ieeexplore.ieee.org/document/5405139/}, doi = {10.1109/JSSC.2009.2035196}, issn = {00189200}, year = {2010}, date = {2010-02-02}, journal = {IEEE Journal of Solid-State Circuits}, volume = {45}, number = {2}, pages = {467-482}, abstract = {We report on a CMOS-based microelectrode array (MEA) featuring 11, 011 metal electrodes and 126 channels, each of which comprises recording and stimulation electronics, for extracellular bidirectional communication with electrogenic cells, such as neurons or cardiomyocytes. The important features include: (i) high spatial resolution at (sub)cellular level with 3150 electrodes per mm2 (electrode diameter 7 um, electrode pitch 18 um); (ii) a reconflgurable routing of the recording sites to the 126 channels; and (iii) low noise levels.}, keywords = {ETH-CMOS-MEA, MEA Technology}, pubstate = {published}, tppubtype = {article} } Close We report on a CMOS-based microelectrode array (MEA) featuring 11, 011 metal electrodes and 126 channels, each of which comprises recording and stimulation electronics, for extracellular bidirectional communication with electrogenic cells, such as neurons or cardiomyocytes. The important features include: (i) high spatial resolution at (sub)cellular level with 3150 electrodes per mm2 (electrode diameter 7 um, electrode pitch 18 um); (ii) a reconflgurable routing of the recording sites to the 126 channels; and (iii) low noise levels. Close http://ieeexplore.ieee.org/document/5405139/ doi:10.1109/JSSC.2009.2035196 Close

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