Publications

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.

All Publications

127 entries « ‹ 2 of 3 › »

2019
	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
	Viswam, Vijay; Bounik, Raziyeh; Shadmani, Amir; Dragas, Jelena; Urwyler, Cedar; Boos, Julia Alicia; Obien, Marie Engelene J; Muller, Jan; Chen, Yihui; Hierlemann, Andreas Impedance Spectroscopy and Electrophysiological Imaging of Cells With a High-Density CMOS Microelectrode Array System Journal Article IEEE Transactions on Biomedical Circuits and Systems, 12 (6), pp. 1356-1368, 2018, ISSN: 1932-4545. Abstract \| Links \| BibTeX \| Tags: HD-MEA @article{Viswam2018, title = {Impedance Spectroscopy and Electrophysiological Imaging of Cells With a High-Density CMOS Microelectrode Array System}, author = {Vijay Viswam and Raziyeh Bounik and Amir Shadmani and Jelena Dragas and Cedar Urwyler and Julia Alicia Boos and Marie Engelene J. Obien and Jan Muller and Yihui Chen and Andreas Hierlemann}, url = {https://ieeexplore.ieee.org/document/8532304}, doi = {10.1109/TBCAS.2018.2881044}, issn = {1932-4545}, year = {2018}, date = {2018-11-12}, journal = {IEEE Transactions on Biomedical Circuits and Systems}, volume = {12}, number = {6}, pages = {1356-1368}, abstract = {A monolithic multi-functional CMOS microelectrode array system was developed that enables label-free electrochemical impedance spectroscopy of cells in vitro at high spatiotemporal resolution. The electrode array includes 59,760 platinum microelectrodes, densely packed within a 4.5 mm × 2.5 mm sensing region at a pitch of 13.5 μm. A total of 32 on-chip lock-in amplifiers can be used to measure the impedance of any arbitrarily chosen subset of electrodes in the array. A sinusoidal voltage, generated by an on-chip waveform generator with a frequency range from 1 Hz to 1 MHz, was applied to the reference electrode. The sensing currents through the selected recording electrodes were amplified, demodulated, filtered, and digitized to obtain the magnitude and phase information of the respective impedances. The circuitry consumes only 412 μW at 3.3 V supply voltage and occupies only 0.1 mm 2 , for each channel. The system also included 2048 extracellular action-potential recording channels on the same chip. Proof of concept measurements of electrical impedance imaging and electrophysiology recording of cardiac cells and brain slices are demonstrated in this paper. Optical and impedance images showed a strong correlation.}, keywords = {HD-MEA}, pubstate = {published}, tppubtype = {article} } Close A monolithic multi-functional CMOS microelectrode array system was developed that enables label-free electrochemical impedance spectroscopy of cells in vitro at high spatiotemporal resolution. The electrode array includes 59,760 platinum microelectrodes, densely packed within a 4.5 mm × 2.5 mm sensing region at a pitch of 13.5 μm. A total of 32 on-chip lock-in amplifiers can be used to measure the impedance of any arbitrarily chosen subset of electrodes in the array. A sinusoidal voltage, generated by an on-chip waveform generator with a frequency range from 1 Hz to 1 MHz, was applied to the reference electrode. The sensing currents through the selected recording electrodes were amplified, demodulated, filtered, and digitized to obtain the magnitude and phase information of the respective impedances. The circuitry consumes only 412 μW at 3.3 V supply voltage and occupies only 0.1 mm 2 , for each channel. The system also included 2048 extracellular action-potential recording channels on the same chip. Proof of concept measurements of electrical impedance imaging and electrophysiology recording of cardiac cells and brain slices are demonstrated in this paper. Optical and impedance images showed a strong correlation. Close https://ieeexplore.ieee.org/document/8532304 doi:10.1109/TBCAS.2018.2881044 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
	Fiscella, Michele; Leary, Noelle; Ronchi, Silvia; Hierlemann, Andreas Electrophysiological phenotype characterization of human iPSC-derived dopaminergic neuronal lines by means of high-resolution microelectrode array Conference Contribution 700.13 , Society for Neuroscience (SfN) Meeting San Diego, CA, USA, 2018. Abstract \| Links \| BibTeX \| Tags: HD-MEA, IPSC @conference{Fiscella2018, title = {Electrophysiological phenotype characterization of human iPSC-derived dopaminergic neuronal lines by means of high-resolution microelectrode array}, author = {Michele Fiscella and Noelle Leary and Silvia Ronchi and Andreas Hierlemann }, url = {https://www.abstractsonline.com/pp8/#!/4649/presentation/24924}, year = {2018}, date = {2018-11-07}, volume = {Contribution 700.13}, address = {San Diego, CA, USA}, organization = {Society for Neuroscience (SfN) Meeting}, abstract = {High-resolution-microelectrode-array (HD-MEA) technology enables to study neuronal dynamics at different scales, ranging from axonal physiology to network connectivity [1]. We have used this HD-MEA technology to characterize and compare the electrical phenotypes of commercially available human dopaminergic neurons (iCell DopaNeurons, MyCell DopaNeurons A53T α-synuclein, Cellular Dynamics International, Madison, WI, US). Furthermore, we have studied the effect of human astrocytes (iCell Astrocytes, Cellular Dynamics International, Madison, WI, US) on neural-culture development. Astrocyte/neuron co-cultures showed higher signal amplitudes and higher firing rates than neural cultures without astrocytes. Adding astrocytes to neural cultures changed the whole culture morphology by promoting cell clustering. Interestingly, astrocyte/neuron co-cultures showed a lower sample-to-sample variability across multiple HD-MEA recordings compared to neural cultures without astrocytes. We compared action potential propagation velocities along axons between dopaminergic A53T α-synuclein neurons and the wild-type isogenic control cell line. We found that in both, wild-type and disease-model neurons, axonal action potential propagation velocities were lower than in rat primary cortical neurons [2]. Furthermore, we found different axonal-action-potential-velocity-development profiles of A53T α-synuclein dopaminergic neurons and the wild-type counterpart. Finally, we were able to precisely evoke action potentials in individual single human neurons by subcellular-resolution electrical stimulation. HD-MEA systems enable to access novel electrophysiological parameters of iPSC-derived neurons, which can be potentially used as biomarkers for phenotype screening and drug testing.}, keywords = {HD-MEA, IPSC}, pubstate = {published}, tppubtype = {conference} } Close High-resolution-microelectrode-array (HD-MEA) technology enables to study neuronal dynamics at different scales, ranging from axonal physiology to network connectivity [1]. We have used this HD-MEA technology to characterize and compare the electrical phenotypes of commercially available human dopaminergic neurons (iCell DopaNeurons, MyCell DopaNeurons A53T α-synuclein, Cellular Dynamics International, Madison, WI, US). Furthermore, we have studied the effect of human astrocytes (iCell Astrocytes, Cellular Dynamics International, Madison, WI, US) on neural-culture development. Astrocyte/neuron co-cultures showed higher signal amplitudes and higher firing rates than neural cultures without astrocytes. Adding astrocytes to neural cultures changed the whole culture morphology by promoting cell clustering. Interestingly, astrocyte/neuron co-cultures showed a lower sample-to-sample variability across multiple HD-MEA recordings compared to neural cultures without astrocytes. We compared action potential propagation velocities along axons between dopaminergic A53T α-synuclein neurons and the wild-type isogenic control cell line. We found that in both, wild-type and disease-model neurons, axonal action potential propagation velocities were lower than in rat primary cortical neurons [2]. Furthermore, we found different axonal-action-potential-velocity-development profiles of A53T α-synuclein dopaminergic neurons and the wild-type counterpart. Finally, we were able to precisely evoke action potentials in individual single human neurons by subcellular-resolution electrical stimulation. HD-MEA systems enable to access novel electrophysiological parameters of iPSC-derived neurons, which can be potentially used as biomarkers for phenotype screening and drug testing. Close https://www.abstractsonline.com/pp8/#!/4649/presentation/24924 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
	Bartram, Julian; Schroter, Manuel; Ronchi, Silvia; Emmenegger, Vishalini; Muller, Jan; Hierlemann, Andreas Mechanisms of homeostatic synaptic plasticity Conference Contribution 037.11 , Society for Neuroscience (SfN) Meeting San Diego, CA, USA, 2018. Abstract \| Links \| BibTeX \| Tags: HD-MEA @conference{Bartram2018, title = {Mechanisms of homeostatic synaptic plasticity}, author = {Julian Bartram and Manuel Schroter and Silvia Ronchi and Vishalini Emmenegger and Jan Muller and Andreas Hierlemann}, url = {https://www.abstractsonline.com/pp8/#!/4649/presentation/3968}, year = {2018}, date = {2018-11-03}, volume = {Contribution 037.11}, address = {San Diego, CA, USA}, organization = {Society for Neuroscience (SfN) Meeting}, abstract = {Homeostatic plasticity is a crucial set of mechanisms acting at typically slow temporal scales in order to stabilize neuronal spike rates. Despite the functional significance of such processes, revealing the precise induction mechanisms has proven to be difficult, as the roles of postsynaptic spiking and synaptic activity are still debated. For a clearer picture of the induction process to emerge, information about synaptic efficacies of multiple inputs needs to be combined with accurate information about spiking activities of the respective presynaptic cells and the postsynaptic cell during the induction of homeostatic plasticity. In this study, we were able to achieve such measurements by performing combined high-density microelectrode array (HD-MEA) and whole-cell patch-clamp recordings in cultures of primary cortical neurons. Homeostatic plasticity was induced by pharmacological alteration of global network spiking and synaptic transmission with TTX or CNQX. Monosynaptic connections between neurons - here with a focus on excitatory connections between pyramidal cells - were identified by correlating presynaptic spiking activity (HD-MEA recordings) with postsynaptic subthreshold responses (patch current-clamp recordings). Presynaptic spiking was spontaneously observed or could be induced via the stimulation capabilities of the HD-MEA system. This experimental approach enabled us to link changes in synaptic efficacy with the respective pre- and postsynaptic spike patterns, recorded during the induction phase, which sheds new light on the rules and mechanisms of homeostatic synaptic plasticity at excitatory synapses. Financial support through the ERC Advanced Grant 694829 “neuroXscales” is gratefully acknowledged.}, keywords = {HD-MEA}, pubstate = {published}, tppubtype = {conference} } Close Homeostatic plasticity is a crucial set of mechanisms acting at typically slow temporal scales in order to stabilize neuronal spike rates. Despite the functional significance of such processes, revealing the precise induction mechanisms has proven to be difficult, as the roles of postsynaptic spiking and synaptic activity are still debated. For a clearer picture of the induction process to emerge, information about synaptic efficacies of multiple inputs needs to be combined with accurate information about spiking activities of the respective presynaptic cells and the postsynaptic cell during the induction of homeostatic plasticity. In this study, we were able to achieve such measurements by performing combined high-density microelectrode array (HD-MEA) and whole-cell patch-clamp recordings in cultures of primary cortical neurons. Homeostatic plasticity was induced by pharmacological alteration of global network spiking and synaptic transmission with TTX or CNQX. Monosynaptic connections between neurons - here with a focus on excitatory connections between pyramidal cells - were identified by correlating presynaptic spiking activity (HD-MEA recordings) with postsynaptic subthreshold responses (patch current-clamp recordings). Presynaptic spiking was spontaneously observed or could be induced via the stimulation capabilities of the HD-MEA system. This experimental approach enabled us to link changes in synaptic efficacy with the respective pre- and postsynaptic spike patterns, recorded during the induction phase, which sheds new light on the rules and mechanisms of homeostatic synaptic plasticity at excitatory synapses. Financial support through the ERC Advanced Grant 694829 “neuroXscales” is gratefully acknowledged. Close https://www.abstractsonline.com/pp8/#!/4649/presentation/3968 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
	Diggelmann, Roland; Fiscella, Michele; Hierlemann, Andreas; Franke, Felix Automatic Spike Sorting Algorithm for High-Density Microelectrode Arrays Journal Article Journal of Neurophysiology, 120 (4), 2018. Abstract \| Links \| BibTeX \| Tags: MEA Technology @article{Diggelmann2018, title = {Automatic Spike Sorting Algorithm for High-Density Microelectrode Arrays}, author = {Roland Diggelmann and Michele Fiscella and Andreas Hierlemann and Felix Franke}, url = {https://www.physiology.org/doi/pdf/10.1152/jn.00803.2017}, doi = {10.1152/jn.00803.2017}, year = {2018}, date = {2018-09-12}, journal = {Journal of Neurophysiology}, volume = {120}, number = {4}, abstract = {High-density microelectrode arrays (HD-MEAs) can be used to record extracellular action potentials from hundreds to thousands of neurons simultaneously. Efficient spike-sorters have to be developed to cope with such large data volumes. Most existing spike sorting methods for single electrodes or small multi-electrodes, however, suffer from the "curse of dimensionality", and cannot be directly applied to recordings with hundreds of electrodes. This holds particularly true for the standard reference spike sorting algorithm, principal-component-analysis-based feature extraction, followed by k-means or expectation maximization clustering, against which most spike-sorters are evaluated. We present a spike sorting algorithm that circumvents the dimensionality problem by sorting local groups of electrodes independently using classical spike sorting approaches. It is scalable to any number of recording electrodes and well suited for parallel computing. The combination of data pre-whitening before the principal-component-analysis-based extraction and a parameter-free clustering algorithm obviated the need for parameter adjustments. We evaluated its performance using surrogate data in which we systematically varied spike amplitudes and spike rates and which were generated by inserting template spikes into the voltage traces of real recordings. In a direct comparison, our algorithm could compete with existing state-of-the-art spike sorters in terms of sensitivity and precision, while parameter adjustment or manual cluster curation were not required.}, keywords = {MEA Technology}, pubstate = {published}, tppubtype = {article} } Close High-density microelectrode arrays (HD-MEAs) can be used to record extracellular action potentials from hundreds to thousands of neurons simultaneously. Efficient spike-sorters have to be developed to cope with such large data volumes. Most existing spike sorting methods for single electrodes or small multi-electrodes, however, suffer from the "curse of dimensionality", and cannot be directly applied to recordings with hundreds of electrodes. This holds particularly true for the standard reference spike sorting algorithm, principal-component-analysis-based feature extraction, followed by k-means or expectation maximization clustering, against which most spike-sorters are evaluated. We present a spike sorting algorithm that circumvents the dimensionality problem by sorting local groups of electrodes independently using classical spike sorting approaches. It is scalable to any number of recording electrodes and well suited for parallel computing. The combination of data pre-whitening before the principal-component-analysis-based extraction and a parameter-free clustering algorithm obviated the need for parameter adjustments. We evaluated its performance using surrogate data in which we systematically varied spike amplitudes and spike rates and which were generated by inserting template spikes into the voltage traces of real recordings. In a direct comparison, our algorithm could compete with existing state-of-the-art spike sorters in terms of sensitivity and precision, while parameter adjustment or manual cluster curation were not required. Close https://www.physiology.org/doi/pdf/10.1152/jn.00803.2017 doi:10.1152/jn.00803.2017 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
	Fiscella, Michele; Leary, Noelle; Ronchi, Silvia; Hierlemann, Andreas Electrophysiological phenotype characterization of human iPSC-derived dopaminergic neuronal lines by means of high-resolution microelelectrode arrays Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: HD-MEA, IPSC @conference{Fiscella2018c, title = {Electrophysiological phenotype characterization of human iPSC-derived dopaminergic neuronal lines by means of high-resolution microelelectrode arrays}, author = {Michele Fiscella and Noelle Leary and Silvia Ronchi and Andreas Hierlemann}, url = {https://www.frontiersin.org/Community/AbstractDetails.aspx?ABS_DOI=10.3389/conf.fncel.2018.38.00014&eid=5473&sname=MEA_Meeting_2018_%7C_11th_International_Meeting_on_Substrate_Integrated_Microelectrode_Arrays}, doi = {10.3389/conf.fncel.2018.38.00014}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {High-resolution-microelectrode-array (MEA) technology enables to study neuronal dynamics at different scales, ranging from axonal physiology to network connectivity (Müller et. al, Lab on a Chip, 2015). We have used this MEA technology to characterize and compare the electrical phenotypes of commercially available human dopaminergic neurons (iCell DopaNeurons, MyCell DopaNeurons A53T α-synuclein, Cellular Dynamics International, Madison, WI, US). Furthermore, we have studied the effect of human astrocytes (iCell Astrocytes, Cellular Dynamics International, Madison, WI, US) on neural culture development. Astrocyte/neuron co-cultures showed higher signal amplitudes and higher firing rates than neural cultures without astrocytes. Adding astrocytes to neural cultures changed the whole culture morphology by promoting cell clustering. Interestingly, astrocyte/neuron co-cultures showed a lower sample-to-sample variability across multiple MEA recording sessions compared to neural cultures without astrocytes. We compared velocities of action potential propagation along axons between dopaminergic A53T α-synuclein neurons and the wild-type isogenic control cell line. We found that in both, wild-type and disease-model neurons, axonal action potential propagation velocities were lower than, for example, in rat primary cortical neurons (Bakkum et. al, Nature Communications, 2013). Furthermore, we found different axonal action-potential-velocity development profiles of A53T α-synuclein dopaminergic neurons and the wild-typecell line. Finally, we were able to precisely and reproducibly evoke action potentials in individual single human IPSC-derived neurons through subcellular-resolution electrical stimulation. High-resolution MEA systems enable to access novel electrophysiological parameters of iPSC-derived neurons, which can be potentially used as biomarkers for phenotype screening and drug testing.}, keywords = {HD-MEA, IPSC}, pubstate = {published}, tppubtype = {conference} } Close High-resolution-microelectrode-array (MEA) technology enables to study neuronal dynamics at different scales, ranging from axonal physiology to network connectivity (Müller et. al, Lab on a Chip, 2015). We have used this MEA technology to characterize and compare the electrical phenotypes of commercially available human dopaminergic neurons (iCell DopaNeurons, MyCell DopaNeurons A53T α-synuclein, Cellular Dynamics International, Madison, WI, US). Furthermore, we have studied the effect of human astrocytes (iCell Astrocytes, Cellular Dynamics International, Madison, WI, US) on neural culture development. Astrocyte/neuron co-cultures showed higher signal amplitudes and higher firing rates than neural cultures without astrocytes. Adding astrocytes to neural cultures changed the whole culture morphology by promoting cell clustering. Interestingly, astrocyte/neuron co-cultures showed a lower sample-to-sample variability across multiple MEA recording sessions compared to neural cultures without astrocytes. We compared velocities of action potential propagation along axons between dopaminergic A53T α-synuclein neurons and the wild-type isogenic control cell line. We found that in both, wild-type and disease-model neurons, axonal action potential propagation velocities were lower than, for example, in rat primary cortical neurons (Bakkum et. al, Nature Communications, 2013). Furthermore, we found different axonal action-potential-velocity development profiles of A53T α-synuclein dopaminergic neurons and the wild-typecell line. Finally, we were able to precisely and reproducibly evoke action potentials in individual single human IPSC-derived neurons through subcellular-resolution electrical stimulation. High-resolution MEA systems enable to access novel electrophysiological parameters of iPSC-derived neurons, which can be potentially used as biomarkers for phenotype screening and drug testing. Close https://www.frontiersin.org/Community/AbstractDetails.aspx?ABS_DOI=10.3389/conf.[...] doi:10.3389/conf.fncel.2018.38.00014 Close
	Urwyler, Cedar; Bounik, Raziyeh; Viswam, Vijay; Hierlemann, Andreas Electrical impedance tomography on high-density microelectrode arrays Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: HD-MEA @conference{Urwyler2018, title = {Electrical impedance tomography on high-density microelectrode arrays}, author = {Cedar Urwyler and Raziyeh Bounik and Vijay Viswam and Andreas Hierlemann }, url = {https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00084/event_abstract}, doi = {10.3389/conf.fncel.2018.38.00084}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {Electrical impedance tomography (EIT) is a non-invasive, label-free imaging technique that enables to reconstruct the conductivity distribution in a body from a series of impedance measurements. Impedance measurements can be used to determine the position, morphology, and growth of cells or tissues, as well as pathological signs, e.g., precancerous tissue conditions (Gersing 1999). The newest high-density microelectrode array (MEA) system developed in our group features 59,760 integrated electrodes (Dragas et al. 2017). The chip features a variety of electrophysiological functions: Action-potential recording (2048 channels), cyclic voltammetry (28 channels), local-field-potential recording (32 channels) and extracellular stimulation (16 channels) [Fig 1A]. The chip can also measure impedance through 32 channels, which enables EIT measurements. We were able to establish a proof of concept for EIT (Viswam et al. 2017). The current goal of this project is to develop an impedance measurement protocol and an appropriate reconstruction algorithm that allow for single-cell-resolution impedance imaging.}, keywords = {HD-MEA}, pubstate = {published}, tppubtype = {conference} } Close Electrical impedance tomography (EIT) is a non-invasive, label-free imaging technique that enables to reconstruct the conductivity distribution in a body from a series of impedance measurements. Impedance measurements can be used to determine the position, morphology, and growth of cells or tissues, as well as pathological signs, e.g., precancerous tissue conditions (Gersing 1999). The newest high-density microelectrode array (MEA) system developed in our group features 59,760 integrated electrodes (Dragas et al. 2017). The chip features a variety of electrophysiological functions: Action-potential recording (2048 channels), cyclic voltammetry (28 channels), local-field-potential recording (32 channels) and extracellular stimulation (16 channels) [Fig 1A]. The chip can also measure impedance through 32 channels, which enables EIT measurements. We were able to establish a proof of concept for EIT (Viswam et al. 2017). The current goal of this project is to develop an impedance measurement protocol and an appropriate reconstruction algorithm that allow for single-cell-resolution impedance imaging. Close https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00084/event_abstract doi:10.3389/conf.fncel.2018.38.00084 Close
	Schroter, Manuel; Girr, Monika; Boos, Julia Alicia; Renner, Magdalena; Gazorpak, Mahshid; Gong, Wei; Bartram, Julian; Muller, Jan; Hierlemann, Andreas Mapping neuronal network dynamics in developing cerebral organoids Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: Neuronal Networks, Organoids @conference{Schroter2018, title = {Mapping neuronal network dynamics in developing cerebral organoids}, author = {Manuel Schroter and Monika Girr and Julia Alicia Boos and Magdalena Renner and Mahshid Gazorpak and Wei Gong and Julian Bartram and Jan Muller and Andreas Hierlemann}, url = {https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00066/event_abstract}, doi = {10.3389/conf.fncel.2018.38.00066}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {Cerebral organoids represent an attractive, novel model system to study early brain development in vitro (Di Lullo and Kriegstein, 2017). Although recent evidence shows that cerebral organoids do recapitulate fundamental milestones of early brain morphogenesis (Lancaster and Knoblich, 2014), the emergence and functionality of brain-organoid neuronal connectivity has not been studied systematically yet. In this study, we apply high-density micro-electrode arrays (MEAs) to record from developing mouse cerebral organoids and characterize their spontaneous neuronal activity. Results provide first evidence on the potential of MEAs as a platform to study the role of spontaneous neuronal activity during brain organoid development and formation of functional microcircuits. }, keywords = {Neuronal Networks, Organoids}, pubstate = {published}, tppubtype = {conference} } Close Cerebral organoids represent an attractive, novel model system to study early brain development in vitro (Di Lullo and Kriegstein, 2017). Although recent evidence shows that cerebral organoids do recapitulate fundamental milestones of early brain morphogenesis (Lancaster and Knoblich, 2014), the emergence and functionality of brain-organoid neuronal connectivity has not been studied systematically yet. In this study, we apply high-density micro-electrode arrays (MEAs) to record from developing mouse cerebral organoids and characterize their spontaneous neuronal activity. Results provide first evidence on the potential of MEAs as a platform to study the role of spontaneous neuronal activity during brain organoid development and formation of functional microcircuits. Close https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00066/event_abstract doi:10.3389/conf.fncel.2018.38.00066 Close
	Bartram, Julian; Schroter, Manuel; Ronchi, Silvia; Emmenegger, Vishalini; Muller, Jan; Hierlemann, Andreas Probing synaptic connectivity and function using high-density microelectrode arrays and whole-cell patch-clamp recordings Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: HD-MEA @conference{Bartram2018b, title = {Probing synaptic connectivity and function using high-density microelectrode arrays and whole-cell patch-clamp recordings}, author = {Julian Bartram and Manuel Schroter and Silvia Ronchi and Vishalini Emmenegger and Jan Muller and Andreas Hierlemann}, url = {https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00085/5473/MEA_Meeting_2018_%7C_11th_International_Meeting_on_Substrate_Integrated_Microelectrode_Arrays/all_events/event_abstract}, doi = {10.3389/conf.fncel.2018.38.00085}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {Synaptic efficacy and synapse number of monosynaptic connections between neurons are often regulated by the spiking activity of the respective pre- and postsynaptic cell. Progress towards a better understanding of the rules and mechanisms that underlie such modifications has been limited due to the difficulties associated with simultaneously studying plasticity at multiple synaptic inputs. Here, we provide a solution to this problem by combining cutting-edge high-density microelectrode array (HD-MEA) technology with the patch-clamp technique. While the latter allows for accurate measurement of postsynaptic currents or potentials, evoked by individual synaptic activation, the HD-MEA technology provides large-scale information about unit activity and allows for selective stimulation of neurons, including multiple presynaptic cells. The proposed approach has been applied to comprehensively examine forms of homeostatic plasticity – a collection of crucial processes acting at different temporal scales in order to stabilize neuronal firing rates. We report on a characterization of classic synaptic scaling operating in mature cortical networks and propose a novel model for the study of homeostatic plasticity during natural network states. }, keywords = {HD-MEA}, pubstate = {published}, tppubtype = {conference} } Close Synaptic efficacy and synapse number of monosynaptic connections between neurons are often regulated by the spiking activity of the respective pre- and postsynaptic cell. Progress towards a better understanding of the rules and mechanisms that underlie such modifications has been limited due to the difficulties associated with simultaneously studying plasticity at multiple synaptic inputs. Here, we provide a solution to this problem by combining cutting-edge high-density microelectrode array (HD-MEA) technology with the patch-clamp technique. While the latter allows for accurate measurement of postsynaptic currents or potentials, evoked by individual synaptic activation, the HD-MEA technology provides large-scale information about unit activity and allows for selective stimulation of neurons, including multiple presynaptic cells. The proposed approach has been applied to comprehensively examine forms of homeostatic plasticity – a collection of crucial processes acting at different temporal scales in order to stabilize neuronal firing rates. We report on a characterization of classic synaptic scaling operating in mature cortical networks and propose a novel model for the study of homeostatic plasticity during natural network states. Close https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00085/5473/MEA_Meeting_20[...] doi:10.3389/conf.fncel.2018.38.00085 Close
	da Drinnenberg Antonia; Franke, Felix; Morikawa Rei Jüttner; Hillier Daniel; Hantz Peter; Hierlemann Andreas; Azeredo Silveira Rava; Roska Botond K; How diverse retinal functions arise from feedback at the first visual synapse Journal Article Neuron, 99 (1), pp. 117-134, 2018. Abstract \| Links \| BibTeX \| Tags: Retina @article{Drinnenberg2018, title = {How diverse retinal functions arise from feedback at the first visual synapse}, author = {Drinnenberg, Antonia; Franke, Felix; Morikawa, Rei K; Jüttner; Hillier, Daniel; Hantz, Peter; Hierlemann, Andreas; Azeredo da Silveira, Rava; Roska, Botond}, url = {https://www.cell.com/neuron/fulltext/S0896-6273(18)30469-0}, doi = {10.1016/j.neuron.2018.06.001}, year = {2018}, date = {2018-06-21}, journal = {Neuron}, volume = {99}, number = {1}, pages = {117-134}, abstract = {Many brain regions contain local interneurons of distinct types. How does an interneuron type contribute to the input-output transformations of a given brain region? We addressed this question in the mouse retina by chemogenetically perturbing horizontal cells, an interneuron type providing feedback at the first visual synapse, while monitoring the light-driven spiking activity in thousands of ganglion cells, the retinal output neurons. We uncovered six reversible perturbation-induced effects in the response dynamics and response range of ganglion cells. The effects were enhancing or suppressive, occurred in different response epochs, and depended on the ganglion cell type. A computational model of the retinal circuitry reproduced all perturbation-induced effects and led us to assign specific functions to horizontal cells with respect to different ganglion cell types. Our combined experimental and theoretical work reveals how a single interneuron type can differentially shape the dynamical properties of distinct output channels of a brain region.}, keywords = {Retina}, pubstate = {published}, tppubtype = {article} } Close Many brain regions contain local interneurons of distinct types. How does an interneuron type contribute to the input-output transformations of a given brain region? We addressed this question in the mouse retina by chemogenetically perturbing horizontal cells, an interneuron type providing feedback at the first visual synapse, while monitoring the light-driven spiking activity in thousands of ganglion cells, the retinal output neurons. We uncovered six reversible perturbation-induced effects in the response dynamics and response range of ganglion cells. The effects were enhancing or suppressive, occurred in different response epochs, and depended on the ganglion cell type. A computational model of the retinal circuitry reproduced all perturbation-induced effects and led us to assign specific functions to horizontal cells with respect to different ganglion cell types. Our combined experimental and theoretical work reveals how a single interneuron type can differentially shape the dynamical properties of distinct output channels of a brain region. Close https://www.cell.com/neuron/fulltext/S0896-6273(18)30469-0 doi:10.1016/j.neuron.2018.06.001 Close
	Fiscella, Michele; Leary, Noelle; Ronchi, Silvia; Hierlemann, Andreas Electrophysiological phenotype characterization of human iPSC-derived dopaminergic neuronal lines by means of high-resolution microelelectrode arrays Conference W-2151 , International Society for Stem Cell Research (ISSCR) Annual Meeting Melbourne, Australia, 2018. Abstract \| Links \| BibTeX \| Tags: HD-MEA, IPSC @conference{Fiscella2018b, title = {Electrophysiological phenotype characterization of human iPSC-derived dopaminergic neuronal lines by means of high-resolution microelelectrode arrays}, author = {Michele Fiscella and Noelle Leary and Silvia Ronchi and Andreas Hierlemann }, url = {http://www.isscr.org/docs/default-source/2018-melbourne-ann-mtng/66670-isscr-abstracts_with-links.pdf?sfvrsn=4&utm_source=ISSCR-Informz&utm_medium=email&utm_campaign=default}, year = {2018}, date = {2018-06-20}, volume = {W-2151}, address = {Melbourne, Australia}, organization = {International Society for Stem Cell Research (ISSCR) Annual Meeting}, abstract = {High-resolution-microelectrode-array (MEA) technology enables to study neuronal dynamics at different scales, ranging from axonal physiology to network connectivity (Müller et. al, Lab on a Chip, 2015). We have used this MEA technology to characterize and compare the electrical phenotypes of commercially available human dopaminergic neurons (iCell DopaNeurons, MyCell DopaNeurons A53T α-synuclein, Cellular Dynamics International, Madison, WI, US). Furthermore, we have studied the effect of human astrocytes (iCell Astrocytes, Cellular Dynamics International, Madison, WI, US) on neural culture development. Astrocyte/neuron co- cultures showed higher signal amplitudes and higher firing rates than neural cultures without astrocytes. Adding astrocytes to neural cultures changed the whole culture morphology by promoting cell clustering. Interestingly, astrocyte/neuron co-cultures showed a lower sample-to-sample variability across multiple MEA recordings compared to neural cultures without astrocytes. We compared action potential propagation velocities along axons between dopaminergic A53T α-synuclein neurons and the wild-type isogenic control cell line. We found that in both, wild-type and disease model neurons, axonal action potential propagation velocities were lower than in rat primary cortical neurons. Furthermore, we found different axonal action potential velocity development profiles of A53T α-synuclein dopaminergic neurons and the wild-type counterpart. Finally, we were able to precisely evoke action potentials in individual single human neurons by subcellular- resolution electrical stimulation. High-resolution MEA systems enable to access novel electrophysiological parameters of iPSC-derived neurons, which can be potentially used as biomarkers for phenotype screening and drug testing.}, keywords = {HD-MEA, IPSC}, pubstate = {published}, tppubtype = {conference} } Close High-resolution-microelectrode-array (MEA) technology enables to study neuronal dynamics at different scales, ranging from axonal physiology to network connectivity (Müller et. al, Lab on a Chip, 2015). We have used this MEA technology to characterize and compare the electrical phenotypes of commercially available human dopaminergic neurons (iCell DopaNeurons, MyCell DopaNeurons A53T α-synuclein, Cellular Dynamics International, Madison, WI, US). Furthermore, we have studied the effect of human astrocytes (iCell Astrocytes, Cellular Dynamics International, Madison, WI, US) on neural culture development. Astrocyte/neuron co- cultures showed higher signal amplitudes and higher firing rates than neural cultures without astrocytes. Adding astrocytes to neural cultures changed the whole culture morphology by promoting cell clustering. Interestingly, astrocyte/neuron co-cultures showed a lower sample-to-sample variability across multiple MEA recordings compared to neural cultures without astrocytes. We compared action potential propagation velocities along axons between dopaminergic A53T α-synuclein neurons and the wild-type isogenic control cell line. We found that in both, wild-type and disease model neurons, axonal action potential propagation velocities were lower than in rat primary cortical neurons. Furthermore, we found different axonal action potential velocity development profiles of A53T α-synuclein dopaminergic neurons and the wild-type counterpart. Finally, we were able to precisely evoke action potentials in individual single human neurons by subcellular- resolution electrical stimulation. High-resolution MEA systems enable to access novel electrophysiological parameters of iPSC-derived neurons, which can be potentially used as biomarkers for phenotype screening and drug testing. Close http://www.isscr.org/docs/default-source/2018-melbourne-ann-mtng/66670-isscr-abs[...] 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
	Viswam, Vijay; Obien, Marie Engelene J; Frey, Urs; Franke, Felix; Hierlemann, Andreas Acquisition of Bioelectrical Signals with Small Electrodes Conference 2017 IEEE Biomedical Circuits and Systems Conference (BioCAS) Turin, Italy, 2017. Abstract \| Links \| BibTeX \| Tags: Electrodes @conference{Viswam2017, title = {Acquisition of Bioelectrical Signals with Small Electrodes}, author = {Vijay Viswam and Marie Engelene J. Obien and Urs Frey and Felix Franke and Andreas Hierlemann}, url = {https://ieeexplore.ieee.org/document/8325216}, doi = {10.1109/BIOCAS.2017.8325216}, year = {2017}, date = {2017-10-19}, address = {Turin, Italy}, organization = {2017 IEEE Biomedical Circuits and Systems Conference (BioCAS)}, abstract = {Although the mechanisms of recording bioelectrical signals from different types of electrogenic cells (neurons, cardiac cells etc.) by means of planar metal electrodes have been extensively studied, the recording characteristics and conditions for very small electrode sizes are not yet established. Here, we present a combined experimental and computational approach to elucidate, how the electrode size influences the recorded signals, and how inherent properties of the electrode, such as impedance, noise, and transmission characteristics shape the signal. We demonstrate that good quality recordings can be achieved with electrode diameters of less than 10 μm, provided that impedance reduction measures have been implemented and provided that a set of requirements for signal amplification has been met.}, keywords = {Electrodes}, pubstate = {published}, tppubtype = {conference} } Close Although the mechanisms of recording bioelectrical signals from different types of electrogenic cells (neurons, cardiac cells etc.) by means of planar metal electrodes have been extensively studied, the recording characteristics and conditions for very small electrode sizes are not yet established. Here, we present a combined experimental and computational approach to elucidate, how the electrode size influences the recorded signals, and how inherent properties of the electrode, such as impedance, noise, and transmission characteristics shape the signal. We demonstrate that good quality recordings can be achieved with electrode diameters of less than 10 μm, provided that impedance reduction measures have been implemented and provided that a set of requirements for signal amplification has been met. Close https://ieeexplore.ieee.org/document/8325216 doi:10.1109/BIOCAS.2017.8325216 Close
	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
	Tajima Satohiro; Mita, Takeshi; Bakkum Douglas Takahashi Hirokazu; Toyoizumi Taro J; Locally embedded presages of global network bursts Journal Article National Academy of Sciences, pp. 1-6, 2017, ISSN: 0027-8424. Abstract \| Links \| BibTeX \| Tags: Neuronal Networks @article{Tajima2017, title = {Locally embedded presages of global network bursts}, author = {Tajima, Satohiro; Mita, Takeshi; Bakkum, Douglas J; Takahashi, Hirokazu; Toyoizumi, Taro}, editor = {Sejnowski, Terrence J}, url = {http://www.pnas.org/content/114/36/9517}, doi = {10.1073/pnas.1705981114 }, issn = {0027-8424}, year = {2017}, date = {2017-08-18}, journal = {National Academy of Sciences}, pages = {1-6}, abstract = {Spontaneous, synchronous bursting of neural population is a widely observed phenomenon in nervous networks, which is considered important for functions and dysfunctions of the brain. However, how the global synchrony across a large number of neurons emerges from an initially nonbursting network state is not fully understood. In this study, we develop a state-space reconstruction method combined with high-resolution recordings of cultured neurons. This method extracts deterministic signatures of upcoming global bursts in “local” dynamics of individual neurons during nonbursting periods. We find that local information within a single-cell time series can compare with or even outperform the global mean-field activity for predicting future global bursts. Moreover, the intercell variability in the burst predictability is found to reflect the network structure realized in the nonbursting periods. These findings suggest that deterministic local dynamics can predict seemingly stochastic global events in self-organized networks, implying the potential applications of the present methodology to detecting locally concentrated early warnings of spontaneous seizure occurrence in the brain.}, keywords = {Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close Spontaneous, synchronous bursting of neural population is a widely observed phenomenon in nervous networks, which is considered important for functions and dysfunctions of the brain. However, how the global synchrony across a large number of neurons emerges from an initially nonbursting network state is not fully understood. In this study, we develop a state-space reconstruction method combined with high-resolution recordings of cultured neurons. This method extracts deterministic signatures of upcoming global bursts in “local” dynamics of individual neurons during nonbursting periods. We find that local information within a single-cell time series can compare with or even outperform the global mean-field activity for predicting future global bursts. Moreover, the intercell variability in the burst predictability is found to reflect the network structure realized in the nonbursting periods. These findings suggest that deterministic local dynamics can predict seemingly stochastic global events in self-organized networks, implying the potential applications of the present methodology to detecting locally concentrated early warnings of spontaneous seizure occurrence in the brain. Close http://www.pnas.org/content/114/36/9517 doi:10.1073/pnas.1705981114 Close
	Shein-Idelson, Mark; Pammer, Lorenz; Hemberger, Mike; Laurent, Gilles Large-scale mapping of cortical synaptic projections with extracellular electrode arrays Journal Article Nature Methods, 14 (9), pp. 882–889, 2017, ISSN: 1548-7091. Abstract \| Links \| BibTeX \| Tags: Brain Slice, MaxOne, Neuronal Networks @article{Shein-Idelson2017, title = {Large-scale mapping of cortical synaptic projections with extracellular electrode arrays}, author = {Mark Shein-Idelson and Lorenz Pammer and Mike Hemberger and Gilles Laurent}, url = {http://www.nature.com/doifinder/10.1038/nmeth.4393}, doi = {10.1038/nmeth.4393}, issn = {1548-7091}, year = {2017}, date = {2017-08-14}, journal = {Nature Methods}, volume = {14}, number = {9}, pages = {882--889}, abstract = {Understanding circuit computation in the nervous system requires sampling activity over large neural populations and maximizing the number of features that can be extracted. By combining planar arrays of extracellular electrodes with the three-layered cortex of turtles, we show that synaptic signals induced along individual axons as well as action potentials can be easily captured. Two types of information can be extracted from these signals, the neuronal subtype (inhibitory or excitatory)—whose identification is more reliable than with traditional measures such as action potential width—and a (partial) spatial map of functional axonal projections from individual neurons. Because our approach is algorithmic, it can be carried out in parallel on hundreds of simultaneously recorded neurons. Combining our approach with soma triangulation, we reveal an axonal projection bias among a population of pyramidal neurons in turtle cortex and confirm this bias through anatomical reconstructions.}, keywords = {Brain Slice, MaxOne, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close Understanding circuit computation in the nervous system requires sampling activity over large neural populations and maximizing the number of features that can be extracted. By combining planar arrays of extracellular electrodes with the three-layered cortex of turtles, we show that synaptic signals induced along individual axons as well as action potentials can be easily captured. Two types of information can be extracted from these signals, the neuronal subtype (inhibitory or excitatory)—whose identification is more reliable than with traditional measures such as action potential width—and a (partial) spatial map of functional axonal projections from individual neurons. Because our approach is algorithmic, it can be carried out in parallel on hundreds of simultaneously recorded neurons. Combining our approach with soma triangulation, we reveal an axonal projection bias among a population of pyramidal neurons in turtle cortex and confirm this bias through anatomical reconstructions. Close http://www.nature.com/doifinder/10.1038/nmeth.4393 doi:10.1038/nmeth.4393 Close
	Obien, Marie Engelene J; Zorzi, Giulio; Hierlemann, Andreas Mapping neuron cluster development based on axonal action potential propagation Conference The 40th Annual Meeting of the Japan Neuroscience Society Chiba, Japan, 2017. BibTeX \| Tags: Action Potential, Neuronal Networks @conference{Obien2017, title = {Mapping neuron cluster development based on axonal action potential propagation}, author = {Marie Engelene J. Obien and Giulio Zorzi and Andreas Hierlemann}, year = {2017}, date = {2017-07-20}, address = {Chiba, Japan}, organization = {The 40th Annual Meeting of the Japan Neuroscience Society}, keywords = {Action Potential, Neuronal Networks}, pubstate = {published}, tppubtype = {conference} } Close
	Diggelmann, Roland; Fiscella, Michele; Hierlemann, Andreas; Franke, Felix Pre-whitening as a means to improve dimensionality reduction and simplify clustering in spike-sorters for multi-electrode recordings Conference 26th Annual Computational Neuroscience Meeting (CNS2017) Antwerp, Belgium , 2017. Abstract \| Links \| BibTeX \| Tags: Spike Sorting @conference{Diggelmann2017, title = {Pre-whitening as a means to improve dimensionality reduction and simplify clustering in spike-sorters for multi-electrode recordings}, author = {Roland Diggelmann and Michele Fiscella and Andreas Hierlemann and Felix Franke}, url = {https://bmcneurosci.biomedcentral.com/articles/10.1186/s12868-017-0371-2}, year = {2017}, date = {2017-07-15}, address = {Antwerp, Belgium }, organization = {26th Annual Computational Neuroscience Meeting (CNS2017)}, abstract = {Spike sorting is the process to extract single neuronal activity from extracellular recordings. It makes use of the fact that spikes from a single neuron feature highly similar waveforms, whereas spikes from different neurons have different waveforms. Clustering algorithms are used to find groups of similar spikes that putatively originated from the same neuron. However, since spike waveforms especially in multi-electrode recordings can have a high dimensionality, their dimensionality needs to be reduced before clustering. Principal component analysis (PCA) is one of the most commonly employed dimensionality reduction methods for this purpose [1]. It reduces the dimensions to those where the variance of the data was highest, presumably those along which the waveforms of separate neurons differ most strongly, However, if the noise is not uniform in all dimensions, high variability can also mean high noise, which would render a dimension useless for discrimination. We, therefore, propose an additional pre-whitening step before PCA and discuss two beneficial effects on the subsequent clustering. We illustrate these effects by using spikes from retinal ganglion cells recorded with high-density multi-electrode arrays (HD-MEA).}, keywords = {Spike Sorting}, pubstate = {published}, tppubtype = {conference} } Close Spike sorting is the process to extract single neuronal activity from extracellular recordings. It makes use of the fact that spikes from a single neuron feature highly similar waveforms, whereas spikes from different neurons have different waveforms. Clustering algorithms are used to find groups of similar spikes that putatively originated from the same neuron. However, since spike waveforms especially in multi-electrode recordings can have a high dimensionality, their dimensionality needs to be reduced before clustering. Principal component analysis (PCA) is one of the most commonly employed dimensionality reduction methods for this purpose [1]. It reduces the dimensions to those where the variance of the data was highest, presumably those along which the waveforms of separate neurons differ most strongly, However, if the noise is not uniform in all dimensions, high variability can also mean high noise, which would render a dimension useless for discrimination. We, therefore, propose an additional pre-whitening step before PCA and discuss two beneficial effects on the subsequent clustering. We illustrate these effects by using spikes from retinal ganglion cells recorded with high-density multi-electrode arrays (HD-MEA). Close https://bmcneurosci.biomedcentral.com/articles/10.1186/s12868-017-0371-2 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
	Obien, Marie Engelene J; Muller, Jan; Boos, Julia Alicia; Bounik, Raziyeh; Fiscella, Michele; Hierlemann, Andreas High-resolution Functional Imaging of Cardiomyocytes Derived from Embryonic Stem Cell Spheroids Conference International Society for Stem Cell Research (ISSCR) Boston, MA, USA, 2017. Links \| BibTeX \| Tags: Cardiomyocytes, HD-MEA @conference{Obien2017b, title = {High-resolution Functional Imaging of Cardiomyocytes Derived from Embryonic Stem Cell Spheroids}, author = {Marie Engelene J. Obien and Jan Muller and Julia Alicia Boos and Raziyeh Bounik and Michele Fiscella and Andreas Hierlemann}, url = {http://www.isscr.org/docs/default-source/am17/64553-isscr-abstracts-proof-3-w-cover.pdf?sfvrsn=2}, year = {2017}, date = {2017-06-14}, address = {Boston, MA, USA}, organization = {International Society for Stem Cell Research (ISSCR) }, keywords = {Cardiomyocytes, HD-MEA}, pubstate = {published}, tppubtype = {conference} } Close http://www.isscr.org/docs/default-source/am17/64553-isscr-abstracts-proof-3-w-co[...] Close
	Fiscella, Michele; Muller, Jan; Hierlemann, Andreas High-resolution Microelectrode Array Platform for Biomarker Discovery and Novel Functional Assays in Human iPSC-derived Neurons Conference International Society for Stem Cell Research (ISSCR) Meeting Boston, MA, USA, 2017. Links \| BibTeX \| Tags: HD-MEA @conference{Fiscella2017, title = {High-resolution Microelectrode Array Platform for Biomarker Discovery and Novel Functional Assays in Human iPSC-derived Neurons}, author = {Michele Fiscella and Jan Muller and Andreas Hierlemann}, url = {http://www.isscr.org/docs/default-source/am17/64553-isscr-abstracts-proof-3-w-cover.pdf?sfvrsn=2}, year = {2017}, date = {2017-06-14}, address = {Boston, MA, USA}, organization = {International Society for Stem Cell Research (ISSCR) Meeting}, keywords = {HD-MEA}, pubstate = {published}, tppubtype = {conference} } Close http://www.isscr.org/docs/default-source/am17/64553-isscr-abstracts-proof-3-w-co[...] Close
	Frey, Urs; Obien, Marie Engelene J; Muller, Jan; Hierlemann, Andreas Technology Trends and Commercialization of High-density Microelectrode Arrays for Advanced In-vitro Electrophysiology Conference IEEE International Symposium on Circuits and Systems (ISCAS Baltimore, MD, USA, 2017, ISSN: 2379-447X. Abstract \| Links \| BibTeX \| Tags: HD-MEA, In-Vitro @conference{Frey2017, title = {Technology Trends and Commercialization of High-density Microelectrode Arrays for Advanced In-vitro Electrophysiology}, author = {Urs Frey and Marie Engelene J. Obien and Jan Muller and Andreas Hierlemann}, url = {https://ieeexplore.ieee.org/document/8050215/}, doi = {10.1109/ISCAS.2017.8050215}, issn = {2379-447X}, year = {2017}, date = {2017-05-28}, address = {Baltimore, MD, USA}, organization = {IEEE International Symposium on Circuits and Systems (ISCAS}, abstract = {Microelectrode arrays (MEAs) enable fast and high-throughput readout of cell's electrical signals. MEAs are currently used for phenotype characterization and drug toxicity/efficacy testing with iPSC-derived neurons and cardiomyocytes. A key advantage of MEAs is the capability to record and stimulate individual neurons at multiple sites simultaneously. We will present ongoing advancements of MEA technology, with a focus on achieving higher quality recordings by means of monolithic co-integration of circuitry on chip by using CMOS technology [1]. Such high-density MEAs with more than 3000 electrodes per mm2 are a suitable tool for capturing neuronal activity across various scales, including axons, somas, dendrites, entire neurons, and networks.}, keywords = {HD-MEA, In-Vitro}, pubstate = {published}, tppubtype = {conference} } Close Microelectrode arrays (MEAs) enable fast and high-throughput readout of cell's electrical signals. MEAs are currently used for phenotype characterization and drug toxicity/efficacy testing with iPSC-derived neurons and cardiomyocytes. A key advantage of MEAs is the capability to record and stimulate individual neurons at multiple sites simultaneously. We will present ongoing advancements of MEA technology, with a focus on achieving higher quality recordings by means of monolithic co-integration of circuitry on chip by using CMOS technology [1]. Such high-density MEAs with more than 3000 electrodes per mm2 are a suitable tool for capturing neuronal activity across various scales, including axons, somas, dendrites, entire neurons, and networks. Close https://ieeexplore.ieee.org/document/8050215/ doi:10.1109/ISCAS.2017.8050215 Close
	Hillier, Daniel; Fiscella, Michele; Drinnenberg, Antonia; Trenholm, Stuart; Rompani, Santiago B; Raics, Zoltan; Katona, Gergely; Jüttner, Josephine; Hierlemann, Andreas; Rozsa, Balazs; Roska, Botond Causal evidence for retina-dependent and -independent visual motion computations in mouse cortex Journal Article Nature Neuroscience, 20 (7), pp. 960–968, 2017, ISSN: 1097-6256. Abstract \| Links \| BibTeX \| Tags: MaxOne, Retina @article{Hillier2017, title = {Causal evidence for retina-dependent and -independent visual motion computations in mouse cortex}, author = {Daniel Hillier and Michele Fiscella and Antonia Drinnenberg and Stuart Trenholm and Santiago B Rompani and Zoltan Raics and Gergely Katona and Josephine Jüttner and Andreas Hierlemann and Balazs Rozsa and Botond Roska}, url = {http://www.nature.com/doifinder/10.1038/nn.4566}, doi = {10.1038/nn.4566}, issn = {1097-6256}, year = {2017}, date = {2017-05-22}, journal = {Nature Neuroscience}, volume = {20}, number = {7}, pages = {960--968}, abstract = {How neuronal computations in the sensory periphery contribute to computations in the cortex is not well understood. We examined this question in the context of visual-motion processing in the retina and primary visual cortex (V1) of mice. We disrupted retinal direction selectivity, either exclusively along the horizontal axis using FRMD7 mutants or along all directions by ablating starburst amacrine cells, and monitored neuronal activity in layer 2/3 of V1 during stimulation with visual motion. In control mice, we found an over-representation of cortical cells preferring posterior visual motion, the dominant motion direction an animal experiences when it moves forward. In mice with disrupted retinal direction selectivity, the over-representation of posterior-motion-preferring cortical cells disappeared, and their responses at higher stimulus speeds were reduced. This work reveals the existence of two functionally distinct, sensory-periphery-dependent and -independent computations of visual motion in the cortex.}, keywords = {MaxOne, Retina}, pubstate = {published}, tppubtype = {article} } Close How neuronal computations in the sensory periphery contribute to computations in the cortex is not well understood. We examined this question in the context of visual-motion processing in the retina and primary visual cortex (V1) of mice. We disrupted retinal direction selectivity, either exclusively along the horizontal axis using FRMD7 mutants or along all directions by ablating starburst amacrine cells, and monitored neuronal activity in layer 2/3 of V1 during stimulation with visual motion. In control mice, we found an over-representation of cortical cells preferring posterior visual motion, the dominant motion direction an animal experiences when it moves forward. In mice with disrupted retinal direction selectivity, the over-representation of posterior-motion-preferring cortical cells disappeared, and their responses at higher stimulus speeds were reduced. This work reveals the existence of two functionally distinct, sensory-periphery-dependent and -independent computations of visual motion in the cortex. Close http://www.nature.com/doifinder/10.1038/nn.4566 doi:10.1038/nn.4566 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
2016
	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, 2016, 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 = {2016}, date = {2016-11-30}, 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
	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
	Lewandowska, Marta K; Radivojevic, Milos; Jäckel, David; Müller, Jan; Hierlemann, Andreas Cortical axons, isolated in channels, display activity-dependent signal modulation as a result of targeted stimulation Journal Article Frontiers in Neuroscience, 10 , pp. 83, 2016, ISSN: 1662453X. Abstract \| Links \| BibTeX \| Tags: MaxOne, Neuronal Networks, u-Tunnels @article{Lewandowska2016, title = {Cortical axons, isolated in channels, display activity-dependent signal modulation as a result of targeted stimulation}, author = {Marta K Lewandowska and Milos Radivojevic and David Jäckel and Jan Müller and Andreas Hierlemann}, url = {https://www.frontiersin.org/articles/10.3389/fnins.2016.00083/full}, doi = {10.3389/fnins.2016.00083}, issn = {1662453X}, year = {2016}, date = {2016-03-07}, journal = {Frontiers in Neuroscience}, volume = {10}, pages = {83}, abstract = {Mammalian cortical axons are extremely thin processes that are difficult to study as a result of their small diameter: they are too narrow to patch while intact, and super-resolution microscopy is needed to resolve single axons. We present a method for studying axonal physiology by pairing a high-density microelectrode array with a microfluidic axonal isolation device, and use it to study activity-dependent modulation of axonal signal propagation evoked by stimulation near the soma. Up to three axonal branches from a single neuron, isolated in different channels, were recorded from simultaneously using 10-20 electrodes per channel. The axonal channels amplified spikes such that propagations of individual signals along tens of electrodes could easily be discerned with high signal to noise. Stimulation from 10 up to 160 Hz demonstrated similar qualitative results from all of the cells studied: extracellular action potential characteristics changed drastically in response to stimulation. Spike height decreased, spike width increased, and latency increased, as a result of reduced propagation velocity, as the number of stimulations and the stimulation frequencies increased. Quantitatively, the strength of these changes manifested itself differently in cells at different frequencies of stimulation. Some cells' signal fidelity fell to 80% already at 10 Hz, while others maintained 80% signal fidelity at 80 Hz. Differences in modulation by axonal branches of the same cell were also seen for different stimulation frequencies, starting at 10 Hz. Potassium ion concentration changes altered the behavior of the cells causing propagation failures at lower concentrations and improving signal fidelity at higher concentrations.}, keywords = {MaxOne, Neuronal Networks, u-Tunnels}, pubstate = {published}, tppubtype = {article} } Close Mammalian cortical axons are extremely thin processes that are difficult to study as a result of their small diameter: they are too narrow to patch while intact, and super-resolution microscopy is needed to resolve single axons. We present a method for studying axonal physiology by pairing a high-density microelectrode array with a microfluidic axonal isolation device, and use it to study activity-dependent modulation of axonal signal propagation evoked by stimulation near the soma. Up to three axonal branches from a single neuron, isolated in different channels, were recorded from simultaneously using 10-20 electrodes per channel. The axonal channels amplified spikes such that propagations of individual signals along tens of electrodes could easily be discerned with high signal to noise. Stimulation from 10 up to 160 Hz demonstrated similar qualitative results from all of the cells studied: extracellular action potential characteristics changed drastically in response to stimulation. Spike height decreased, spike width increased, and latency increased, as a result of reduced propagation velocity, as the number of stimulations and the stimulation frequencies increased. Quantitatively, the strength of these changes manifested itself differently in cells at different frequencies of stimulation. Some cells' signal fidelity fell to 80% already at 10 Hz, while others maintained 80% signal fidelity at 80 Hz. Differences in modulation by axonal branches of the same cell were also seen for different stimulation frequencies, starting at 10 Hz. Potassium ion concentration changes altered the behavior of the cells causing propagation failures at lower concentrations and improving signal fidelity at higher concentrations. Close https://www.frontiersin.org/articles/10.3389/fnins.2016.00083/full doi:10.3389/fnins.2016.00083 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
	Müller, Jan; Ballini, Marco; Livi, Paolo; Chen, Yihui; Radivojevic, Milos; Shadmani, Amir; Viswam, Vijay; Jones, Ian L; Fiscella, Michele; Diggelmann, Roland; Stettler, Alexander; Frey, Urs; Bakkum, Douglas J; Hierlemann, Andreas High-resolution CMOS MEA platform to study neurons at subcellular, cellular, and network levels Journal Article Lab Chip, 15 (13), pp. 2767-2780, 2015, ISSN: 1473-0197. Abstract \| Links \| BibTeX \| Tags: MaxOne, Neuronal Networks @article{Muller2015, title = {High-resolution CMOS MEA platform to study neurons at subcellular, cellular, and network levels}, author = {Jan Müller and Marco Ballini and Paolo Livi and Yihui Chen and Milos Radivojevic and Amir Shadmani and Vijay Viswam and Ian L Jones and Michele Fiscella and Roland Diggelmann and Alexander Stettler and Urs Frey and Douglas J Bakkum and Andreas Hierlemann}, url = {http://pubs.rsc.org/en/Content/ArticleLanding/2015/LC/C5LC00133A#!divAbstract}, doi = {10.1039/C5LC00133A}, issn = {1473-0197}, year = {2015}, date = {2015-07-07}, journal = {Lab Chip}, volume = {15}, number = {13}, pages = {2767-2780}, publisher = {Royal Society of Chemistry}, abstract = {Studies on information processing and learning properties of neuronal networks would benefit from simultaneous and parallel access to the activity of a large fraction of all neurons in such networks. Here, we present a CMOS-based device, capable of simultaneously recording the electrical activity of over a thousand cells in in vitro neuronal networks. The device provides sufficiently high spatiotemporal resolution to enable, at the same time, access to neuronal preparations on subcellular, cellular, and network level. The key feature is a rapidly reconfigurable array of 26 400 microelectrodes arranged at low pitch (17.5 um) within a large overall sensing area (3.85 × 2.10 mm2). An arbitrary subset of the electrodes can be simultaneously connected to 1024 low-noise readout channels as well as 32 stimulation units. Each electrode or electrode subset can be used to electrically stimulate or record the signals of virtually any neuron on the array. We demonstrate the applicability and potential of this device for various different experimental paradigms: large-scale recordings from whole networks of neurons as well as investigations of axonal properties of individual neurons.}, keywords = {MaxOne, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close Studies on information processing and learning properties of neuronal networks would benefit from simultaneous and parallel access to the activity of a large fraction of all neurons in such networks. Here, we present a CMOS-based device, capable of simultaneously recording the electrical activity of over a thousand cells in in vitro neuronal networks. The device provides sufficiently high spatiotemporal resolution to enable, at the same time, access to neuronal preparations on subcellular, cellular, and network level. The key feature is a rapidly reconfigurable array of 26 400 microelectrodes arranged at low pitch (17.5 um) within a large overall sensing area (3.85 × 2.10 mm2). An arbitrary subset of the electrodes can be simultaneously connected to 1024 low-noise readout channels as well as 32 stimulation units. Each electrode or electrode subset can be used to electrically stimulate or record the signals of virtually any neuron on the array. We demonstrate the applicability and potential of this device for various different experimental paradigms: large-scale recordings from whole networks of neurons as well as investigations of axonal properties of individual neurons. Close http://pubs.rsc.org/en/Content/ArticleLanding/2015/LC/C5LC00133A#!divAbstract doi:10.1039/C5LC00133A Close
	Krol, Jacek; Krol, Ilona; Alvarez, Claudia Patricia Patino; Fiscella, Michele; Hierlemann, Andreas; Roska, Botond; Filipowicz, Witold A network comprising short and long noncoding RNAs and RNA helicase controls mouse retina architecture. Journal Article Nature Communications, 6 , pp. 7305, 2015, ISSN: 2041-1723. Abstract \| Links \| BibTeX \| Tags: MaxOne, Retina @article{Krol2015, title = {A network comprising short and long noncoding RNAs and RNA helicase controls mouse retina architecture.}, author = {Jacek Krol and Ilona Krol and Claudia Patricia Patino Alvarez and Michele Fiscella and Andreas Hierlemann and Botond Roska and Witold Filipowicz}, url = {https://www.nature.com/articles/ncomms8305}, doi = {10.1038/ncomms8305}, issn = {2041-1723}, year = {2015}, date = {2015-06-04}, journal = {Nature Communications}, volume = {6}, pages = {7305}, publisher = {Nature Publishing Group}, abstract = {Brain regions, such as the cortex and retina, are composed of layers of uniform thickness. The molecular mechanism that controls this uniformity is not well understood. Here we show that during mouse postnatal development the timed expression of Rncr4, a retina-specific long noncoding RNA, regulates the similarly timed processing of pri-miR-183/96/182, which is repressed at an earlier developmental stage by RNA helicase Ddx3x. Shifting the timing of mature miR-183/96/182 accumulation or interfering with Ddx3x expression leads to the disorganization of retinal architecture, with the photoreceptor layer being most affected. We identify Crb1, a component of the adhesion belt between glial and photoreceptor cells, as a link between Rncr4-regulated miRNA metabolism and uniform retina layering. Our results suggest that the precise timing of glia-neuron interaction controlled by noncoding RNAs and Ddx3x is important for the even distribution of cells across layers.}, keywords = {MaxOne, Retina}, pubstate = {published}, tppubtype = {article} } Close Brain regions, such as the cortex and retina, are composed of layers of uniform thickness. The molecular mechanism that controls this uniformity is not well understood. Here we show that during mouse postnatal development the timed expression of Rncr4, a retina-specific long noncoding RNA, regulates the similarly timed processing of pri-miR-183/96/182, which is repressed at an earlier developmental stage by RNA helicase Ddx3x. Shifting the timing of mature miR-183/96/182 accumulation or interfering with Ddx3x expression leads to the disorganization of retinal architecture, with the photoreceptor layer being most affected. We identify Crb1, a component of the adhesion belt between glial and photoreceptor cells, as a link between Rncr4-regulated miRNA metabolism and uniform retina layering. Our results suggest that the precise timing of glia-neuron interaction controlled by noncoding RNAs and Ddx3x is important for the even distribution of cells across layers. Close https://www.nature.com/articles/ncomms8305 doi:10.1038/ncomms8305 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

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2019
	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
	Viswam, Vijay; Bounik, Raziyeh; Shadmani, Amir; Dragas, Jelena; Urwyler, Cedar; Boos, Julia Alicia; Obien, Marie Engelene J; Muller, Jan; Chen, Yihui; Hierlemann, Andreas Impedance Spectroscopy and Electrophysiological Imaging of Cells With a High-Density CMOS Microelectrode Array System Journal Article IEEE Transactions on Biomedical Circuits and Systems, 12 (6), pp. 1356-1368, 2018, ISSN: 1932-4545. Abstract \| Links \| BibTeX \| Tags: HD-MEA @article{Viswam2018, title = {Impedance Spectroscopy and Electrophysiological Imaging of Cells With a High-Density CMOS Microelectrode Array System}, author = {Vijay Viswam and Raziyeh Bounik and Amir Shadmani and Jelena Dragas and Cedar Urwyler and Julia Alicia Boos and Marie Engelene J. Obien and Jan Muller and Yihui Chen and Andreas Hierlemann}, url = {https://ieeexplore.ieee.org/document/8532304}, doi = {10.1109/TBCAS.2018.2881044}, issn = {1932-4545}, year = {2018}, date = {2018-11-12}, journal = {IEEE Transactions on Biomedical Circuits and Systems}, volume = {12}, number = {6}, pages = {1356-1368}, abstract = {A monolithic multi-functional CMOS microelectrode array system was developed that enables label-free electrochemical impedance spectroscopy of cells in vitro at high spatiotemporal resolution. The electrode array includes 59,760 platinum microelectrodes, densely packed within a 4.5 mm × 2.5 mm sensing region at a pitch of 13.5 μm. A total of 32 on-chip lock-in amplifiers can be used to measure the impedance of any arbitrarily chosen subset of electrodes in the array. A sinusoidal voltage, generated by an on-chip waveform generator with a frequency range from 1 Hz to 1 MHz, was applied to the reference electrode. The sensing currents through the selected recording electrodes were amplified, demodulated, filtered, and digitized to obtain the magnitude and phase information of the respective impedances. The circuitry consumes only 412 μW at 3.3 V supply voltage and occupies only 0.1 mm 2 , for each channel. The system also included 2048 extracellular action-potential recording channels on the same chip. Proof of concept measurements of electrical impedance imaging and electrophysiology recording of cardiac cells and brain slices are demonstrated in this paper. Optical and impedance images showed a strong correlation.}, keywords = {HD-MEA}, pubstate = {published}, tppubtype = {article} } Close A monolithic multi-functional CMOS microelectrode array system was developed that enables label-free electrochemical impedance spectroscopy of cells in vitro at high spatiotemporal resolution. The electrode array includes 59,760 platinum microelectrodes, densely packed within a 4.5 mm × 2.5 mm sensing region at a pitch of 13.5 μm. A total of 32 on-chip lock-in amplifiers can be used to measure the impedance of any arbitrarily chosen subset of electrodes in the array. A sinusoidal voltage, generated by an on-chip waveform generator with a frequency range from 1 Hz to 1 MHz, was applied to the reference electrode. The sensing currents through the selected recording electrodes were amplified, demodulated, filtered, and digitized to obtain the magnitude and phase information of the respective impedances. The circuitry consumes only 412 μW at 3.3 V supply voltage and occupies only 0.1 mm 2 , for each channel. The system also included 2048 extracellular action-potential recording channels on the same chip. Proof of concept measurements of electrical impedance imaging and electrophysiology recording of cardiac cells and brain slices are demonstrated in this paper. Optical and impedance images showed a strong correlation. Close https://ieeexplore.ieee.org/document/8532304 doi:10.1109/TBCAS.2018.2881044 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
	Fiscella, Michele; Leary, Noelle; Ronchi, Silvia; Hierlemann, Andreas Electrophysiological phenotype characterization of human iPSC-derived dopaminergic neuronal lines by means of high-resolution microelectrode array Conference Contribution 700.13 , Society for Neuroscience (SfN) Meeting San Diego, CA, USA, 2018. Abstract \| Links \| BibTeX \| Tags: HD-MEA, IPSC @conference{Fiscella2018, title = {Electrophysiological phenotype characterization of human iPSC-derived dopaminergic neuronal lines by means of high-resolution microelectrode array}, author = {Michele Fiscella and Noelle Leary and Silvia Ronchi and Andreas Hierlemann }, url = {https://www.abstractsonline.com/pp8/#!/4649/presentation/24924}, year = {2018}, date = {2018-11-07}, volume = {Contribution 700.13}, address = {San Diego, CA, USA}, organization = {Society for Neuroscience (SfN) Meeting}, abstract = {High-resolution-microelectrode-array (HD-MEA) technology enables to study neuronal dynamics at different scales, ranging from axonal physiology to network connectivity [1]. We have used this HD-MEA technology to characterize and compare the electrical phenotypes of commercially available human dopaminergic neurons (iCell DopaNeurons, MyCell DopaNeurons A53T α-synuclein, Cellular Dynamics International, Madison, WI, US). Furthermore, we have studied the effect of human astrocytes (iCell Astrocytes, Cellular Dynamics International, Madison, WI, US) on neural-culture development. Astrocyte/neuron co-cultures showed higher signal amplitudes and higher firing rates than neural cultures without astrocytes. Adding astrocytes to neural cultures changed the whole culture morphology by promoting cell clustering. Interestingly, astrocyte/neuron co-cultures showed a lower sample-to-sample variability across multiple HD-MEA recordings compared to neural cultures without astrocytes. We compared action potential propagation velocities along axons between dopaminergic A53T α-synuclein neurons and the wild-type isogenic control cell line. We found that in both, wild-type and disease-model neurons, axonal action potential propagation velocities were lower than in rat primary cortical neurons [2]. Furthermore, we found different axonal-action-potential-velocity-development profiles of A53T α-synuclein dopaminergic neurons and the wild-type counterpart. Finally, we were able to precisely evoke action potentials in individual single human neurons by subcellular-resolution electrical stimulation. HD-MEA systems enable to access novel electrophysiological parameters of iPSC-derived neurons, which can be potentially used as biomarkers for phenotype screening and drug testing.}, keywords = {HD-MEA, IPSC}, pubstate = {published}, tppubtype = {conference} } Close High-resolution-microelectrode-array (HD-MEA) technology enables to study neuronal dynamics at different scales, ranging from axonal physiology to network connectivity [1]. We have used this HD-MEA technology to characterize and compare the electrical phenotypes of commercially available human dopaminergic neurons (iCell DopaNeurons, MyCell DopaNeurons A53T α-synuclein, Cellular Dynamics International, Madison, WI, US). Furthermore, we have studied the effect of human astrocytes (iCell Astrocytes, Cellular Dynamics International, Madison, WI, US) on neural-culture development. Astrocyte/neuron co-cultures showed higher signal amplitudes and higher firing rates than neural cultures without astrocytes. Adding astrocytes to neural cultures changed the whole culture morphology by promoting cell clustering. Interestingly, astrocyte/neuron co-cultures showed a lower sample-to-sample variability across multiple HD-MEA recordings compared to neural cultures without astrocytes. We compared action potential propagation velocities along axons between dopaminergic A53T α-synuclein neurons and the wild-type isogenic control cell line. We found that in both, wild-type and disease-model neurons, axonal action potential propagation velocities were lower than in rat primary cortical neurons [2]. Furthermore, we found different axonal-action-potential-velocity-development profiles of A53T α-synuclein dopaminergic neurons and the wild-type counterpart. Finally, we were able to precisely evoke action potentials in individual single human neurons by subcellular-resolution electrical stimulation. HD-MEA systems enable to access novel electrophysiological parameters of iPSC-derived neurons, which can be potentially used as biomarkers for phenotype screening and drug testing. Close https://www.abstractsonline.com/pp8/#!/4649/presentation/24924 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
	Bartram, Julian; Schroter, Manuel; Ronchi, Silvia; Emmenegger, Vishalini; Muller, Jan; Hierlemann, Andreas Mechanisms of homeostatic synaptic plasticity Conference Contribution 037.11 , Society for Neuroscience (SfN) Meeting San Diego, CA, USA, 2018. Abstract \| Links \| BibTeX \| Tags: HD-MEA @conference{Bartram2018, title = {Mechanisms of homeostatic synaptic plasticity}, author = {Julian Bartram and Manuel Schroter and Silvia Ronchi and Vishalini Emmenegger and Jan Muller and Andreas Hierlemann}, url = {https://www.abstractsonline.com/pp8/#!/4649/presentation/3968}, year = {2018}, date = {2018-11-03}, volume = {Contribution 037.11}, address = {San Diego, CA, USA}, organization = {Society for Neuroscience (SfN) Meeting}, abstract = {Homeostatic plasticity is a crucial set of mechanisms acting at typically slow temporal scales in order to stabilize neuronal spike rates. Despite the functional significance of such processes, revealing the precise induction mechanisms has proven to be difficult, as the roles of postsynaptic spiking and synaptic activity are still debated. For a clearer picture of the induction process to emerge, information about synaptic efficacies of multiple inputs needs to be combined with accurate information about spiking activities of the respective presynaptic cells and the postsynaptic cell during the induction of homeostatic plasticity. In this study, we were able to achieve such measurements by performing combined high-density microelectrode array (HD-MEA) and whole-cell patch-clamp recordings in cultures of primary cortical neurons. Homeostatic plasticity was induced by pharmacological alteration of global network spiking and synaptic transmission with TTX or CNQX. Monosynaptic connections between neurons - here with a focus on excitatory connections between pyramidal cells - were identified by correlating presynaptic spiking activity (HD-MEA recordings) with postsynaptic subthreshold responses (patch current-clamp recordings). Presynaptic spiking was spontaneously observed or could be induced via the stimulation capabilities of the HD-MEA system. This experimental approach enabled us to link changes in synaptic efficacy with the respective pre- and postsynaptic spike patterns, recorded during the induction phase, which sheds new light on the rules and mechanisms of homeostatic synaptic plasticity at excitatory synapses. Financial support through the ERC Advanced Grant 694829 “neuroXscales” is gratefully acknowledged.}, keywords = {HD-MEA}, pubstate = {published}, tppubtype = {conference} } Close Homeostatic plasticity is a crucial set of mechanisms acting at typically slow temporal scales in order to stabilize neuronal spike rates. Despite the functional significance of such processes, revealing the precise induction mechanisms has proven to be difficult, as the roles of postsynaptic spiking and synaptic activity are still debated. For a clearer picture of the induction process to emerge, information about synaptic efficacies of multiple inputs needs to be combined with accurate information about spiking activities of the respective presynaptic cells and the postsynaptic cell during the induction of homeostatic plasticity. In this study, we were able to achieve such measurements by performing combined high-density microelectrode array (HD-MEA) and whole-cell patch-clamp recordings in cultures of primary cortical neurons. Homeostatic plasticity was induced by pharmacological alteration of global network spiking and synaptic transmission with TTX or CNQX. Monosynaptic connections between neurons - here with a focus on excitatory connections between pyramidal cells - were identified by correlating presynaptic spiking activity (HD-MEA recordings) with postsynaptic subthreshold responses (patch current-clamp recordings). Presynaptic spiking was spontaneously observed or could be induced via the stimulation capabilities of the HD-MEA system. This experimental approach enabled us to link changes in synaptic efficacy with the respective pre- and postsynaptic spike patterns, recorded during the induction phase, which sheds new light on the rules and mechanisms of homeostatic synaptic plasticity at excitatory synapses. Financial support through the ERC Advanced Grant 694829 “neuroXscales” is gratefully acknowledged. Close https://www.abstractsonline.com/pp8/#!/4649/presentation/3968 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
	Diggelmann, Roland; Fiscella, Michele; Hierlemann, Andreas; Franke, Felix Automatic Spike Sorting Algorithm for High-Density Microelectrode Arrays Journal Article Journal of Neurophysiology, 120 (4), 2018. Abstract \| Links \| BibTeX \| Tags: MEA Technology @article{Diggelmann2018, title = {Automatic Spike Sorting Algorithm for High-Density Microelectrode Arrays}, author = {Roland Diggelmann and Michele Fiscella and Andreas Hierlemann and Felix Franke}, url = {https://www.physiology.org/doi/pdf/10.1152/jn.00803.2017}, doi = {10.1152/jn.00803.2017}, year = {2018}, date = {2018-09-12}, journal = {Journal of Neurophysiology}, volume = {120}, number = {4}, abstract = {High-density microelectrode arrays (HD-MEAs) can be used to record extracellular action potentials from hundreds to thousands of neurons simultaneously. Efficient spike-sorters have to be developed to cope with such large data volumes. Most existing spike sorting methods for single electrodes or small multi-electrodes, however, suffer from the "curse of dimensionality", and cannot be directly applied to recordings with hundreds of electrodes. This holds particularly true for the standard reference spike sorting algorithm, principal-component-analysis-based feature extraction, followed by k-means or expectation maximization clustering, against which most spike-sorters are evaluated. We present a spike sorting algorithm that circumvents the dimensionality problem by sorting local groups of electrodes independently using classical spike sorting approaches. It is scalable to any number of recording electrodes and well suited for parallel computing. The combination of data pre-whitening before the principal-component-analysis-based extraction and a parameter-free clustering algorithm obviated the need for parameter adjustments. We evaluated its performance using surrogate data in which we systematically varied spike amplitudes and spike rates and which were generated by inserting template spikes into the voltage traces of real recordings. In a direct comparison, our algorithm could compete with existing state-of-the-art spike sorters in terms of sensitivity and precision, while parameter adjustment or manual cluster curation were not required.}, keywords = {MEA Technology}, pubstate = {published}, tppubtype = {article} } Close High-density microelectrode arrays (HD-MEAs) can be used to record extracellular action potentials from hundreds to thousands of neurons simultaneously. Efficient spike-sorters have to be developed to cope with such large data volumes. Most existing spike sorting methods for single electrodes or small multi-electrodes, however, suffer from the "curse of dimensionality", and cannot be directly applied to recordings with hundreds of electrodes. This holds particularly true for the standard reference spike sorting algorithm, principal-component-analysis-based feature extraction, followed by k-means or expectation maximization clustering, against which most spike-sorters are evaluated. We present a spike sorting algorithm that circumvents the dimensionality problem by sorting local groups of electrodes independently using classical spike sorting approaches. It is scalable to any number of recording electrodes and well suited for parallel computing. The combination of data pre-whitening before the principal-component-analysis-based extraction and a parameter-free clustering algorithm obviated the need for parameter adjustments. We evaluated its performance using surrogate data in which we systematically varied spike amplitudes and spike rates and which were generated by inserting template spikes into the voltage traces of real recordings. In a direct comparison, our algorithm could compete with existing state-of-the-art spike sorters in terms of sensitivity and precision, while parameter adjustment or manual cluster curation were not required. Close https://www.physiology.org/doi/pdf/10.1152/jn.00803.2017 doi:10.1152/jn.00803.2017 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
	Fiscella, Michele; Leary, Noelle; Ronchi, Silvia; Hierlemann, Andreas Electrophysiological phenotype characterization of human iPSC-derived dopaminergic neuronal lines by means of high-resolution microelelectrode arrays Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: HD-MEA, IPSC @conference{Fiscella2018c, title = {Electrophysiological phenotype characterization of human iPSC-derived dopaminergic neuronal lines by means of high-resolution microelelectrode arrays}, author = {Michele Fiscella and Noelle Leary and Silvia Ronchi and Andreas Hierlemann}, url = {https://www.frontiersin.org/Community/AbstractDetails.aspx?ABS_DOI=10.3389/conf.fncel.2018.38.00014&eid=5473&sname=MEA_Meeting_2018_%7C_11th_International_Meeting_on_Substrate_Integrated_Microelectrode_Arrays}, doi = {10.3389/conf.fncel.2018.38.00014}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {High-resolution-microelectrode-array (MEA) technology enables to study neuronal dynamics at different scales, ranging from axonal physiology to network connectivity (Müller et. al, Lab on a Chip, 2015). We have used this MEA technology to characterize and compare the electrical phenotypes of commercially available human dopaminergic neurons (iCell DopaNeurons, MyCell DopaNeurons A53T α-synuclein, Cellular Dynamics International, Madison, WI, US). Furthermore, we have studied the effect of human astrocytes (iCell Astrocytes, Cellular Dynamics International, Madison, WI, US) on neural culture development. Astrocyte/neuron co-cultures showed higher signal amplitudes and higher firing rates than neural cultures without astrocytes. Adding astrocytes to neural cultures changed the whole culture morphology by promoting cell clustering. Interestingly, astrocyte/neuron co-cultures showed a lower sample-to-sample variability across multiple MEA recording sessions compared to neural cultures without astrocytes. We compared velocities of action potential propagation along axons between dopaminergic A53T α-synuclein neurons and the wild-type isogenic control cell line. We found that in both, wild-type and disease-model neurons, axonal action potential propagation velocities were lower than, for example, in rat primary cortical neurons (Bakkum et. al, Nature Communications, 2013). Furthermore, we found different axonal action-potential-velocity development profiles of A53T α-synuclein dopaminergic neurons and the wild-typecell line. Finally, we were able to precisely and reproducibly evoke action potentials in individual single human IPSC-derived neurons through subcellular-resolution electrical stimulation. High-resolution MEA systems enable to access novel electrophysiological parameters of iPSC-derived neurons, which can be potentially used as biomarkers for phenotype screening and drug testing.}, keywords = {HD-MEA, IPSC}, pubstate = {published}, tppubtype = {conference} } Close High-resolution-microelectrode-array (MEA) technology enables to study neuronal dynamics at different scales, ranging from axonal physiology to network connectivity (Müller et. al, Lab on a Chip, 2015). We have used this MEA technology to characterize and compare the electrical phenotypes of commercially available human dopaminergic neurons (iCell DopaNeurons, MyCell DopaNeurons A53T α-synuclein, Cellular Dynamics International, Madison, WI, US). Furthermore, we have studied the effect of human astrocytes (iCell Astrocytes, Cellular Dynamics International, Madison, WI, US) on neural culture development. Astrocyte/neuron co-cultures showed higher signal amplitudes and higher firing rates than neural cultures without astrocytes. Adding astrocytes to neural cultures changed the whole culture morphology by promoting cell clustering. Interestingly, astrocyte/neuron co-cultures showed a lower sample-to-sample variability across multiple MEA recording sessions compared to neural cultures without astrocytes. We compared velocities of action potential propagation along axons between dopaminergic A53T α-synuclein neurons and the wild-type isogenic control cell line. We found that in both, wild-type and disease-model neurons, axonal action potential propagation velocities were lower than, for example, in rat primary cortical neurons (Bakkum et. al, Nature Communications, 2013). Furthermore, we found different axonal action-potential-velocity development profiles of A53T α-synuclein dopaminergic neurons and the wild-typecell line. Finally, we were able to precisely and reproducibly evoke action potentials in individual single human IPSC-derived neurons through subcellular-resolution electrical stimulation. High-resolution MEA systems enable to access novel electrophysiological parameters of iPSC-derived neurons, which can be potentially used as biomarkers for phenotype screening and drug testing. Close https://www.frontiersin.org/Community/AbstractDetails.aspx?ABS_DOI=10.3389/conf.[...] doi:10.3389/conf.fncel.2018.38.00014 Close
	Urwyler, Cedar; Bounik, Raziyeh; Viswam, Vijay; Hierlemann, Andreas Electrical impedance tomography on high-density microelectrode arrays Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: HD-MEA @conference{Urwyler2018, title = {Electrical impedance tomography on high-density microelectrode arrays}, author = {Cedar Urwyler and Raziyeh Bounik and Vijay Viswam and Andreas Hierlemann }, url = {https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00084/event_abstract}, doi = {10.3389/conf.fncel.2018.38.00084}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {Electrical impedance tomography (EIT) is a non-invasive, label-free imaging technique that enables to reconstruct the conductivity distribution in a body from a series of impedance measurements. Impedance measurements can be used to determine the position, morphology, and growth of cells or tissues, as well as pathological signs, e.g., precancerous tissue conditions (Gersing 1999). The newest high-density microelectrode array (MEA) system developed in our group features 59,760 integrated electrodes (Dragas et al. 2017). The chip features a variety of electrophysiological functions: Action-potential recording (2048 channels), cyclic voltammetry (28 channels), local-field-potential recording (32 channels) and extracellular stimulation (16 channels) [Fig 1A]. The chip can also measure impedance through 32 channels, which enables EIT measurements. We were able to establish a proof of concept for EIT (Viswam et al. 2017). The current goal of this project is to develop an impedance measurement protocol and an appropriate reconstruction algorithm that allow for single-cell-resolution impedance imaging.}, keywords = {HD-MEA}, pubstate = {published}, tppubtype = {conference} } Close Electrical impedance tomography (EIT) is a non-invasive, label-free imaging technique that enables to reconstruct the conductivity distribution in a body from a series of impedance measurements. Impedance measurements can be used to determine the position, morphology, and growth of cells or tissues, as well as pathological signs, e.g., precancerous tissue conditions (Gersing 1999). The newest high-density microelectrode array (MEA) system developed in our group features 59,760 integrated electrodes (Dragas et al. 2017). The chip features a variety of electrophysiological functions: Action-potential recording (2048 channels), cyclic voltammetry (28 channels), local-field-potential recording (32 channels) and extracellular stimulation (16 channels) [Fig 1A]. The chip can also measure impedance through 32 channels, which enables EIT measurements. We were able to establish a proof of concept for EIT (Viswam et al. 2017). The current goal of this project is to develop an impedance measurement protocol and an appropriate reconstruction algorithm that allow for single-cell-resolution impedance imaging. Close https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00084/event_abstract doi:10.3389/conf.fncel.2018.38.00084 Close
	Schroter, Manuel; Girr, Monika; Boos, Julia Alicia; Renner, Magdalena; Gazorpak, Mahshid; Gong, Wei; Bartram, Julian; Muller, Jan; Hierlemann, Andreas Mapping neuronal network dynamics in developing cerebral organoids Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: Neuronal Networks, Organoids @conference{Schroter2018, title = {Mapping neuronal network dynamics in developing cerebral organoids}, author = {Manuel Schroter and Monika Girr and Julia Alicia Boos and Magdalena Renner and Mahshid Gazorpak and Wei Gong and Julian Bartram and Jan Muller and Andreas Hierlemann}, url = {https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00066/event_abstract}, doi = {10.3389/conf.fncel.2018.38.00066}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {Cerebral organoids represent an attractive, novel model system to study early brain development in vitro (Di Lullo and Kriegstein, 2017). Although recent evidence shows that cerebral organoids do recapitulate fundamental milestones of early brain morphogenesis (Lancaster and Knoblich, 2014), the emergence and functionality of brain-organoid neuronal connectivity has not been studied systematically yet. In this study, we apply high-density micro-electrode arrays (MEAs) to record from developing mouse cerebral organoids and characterize their spontaneous neuronal activity. Results provide first evidence on the potential of MEAs as a platform to study the role of spontaneous neuronal activity during brain organoid development and formation of functional microcircuits. }, keywords = {Neuronal Networks, Organoids}, pubstate = {published}, tppubtype = {conference} } Close Cerebral organoids represent an attractive, novel model system to study early brain development in vitro (Di Lullo and Kriegstein, 2017). Although recent evidence shows that cerebral organoids do recapitulate fundamental milestones of early brain morphogenesis (Lancaster and Knoblich, 2014), the emergence and functionality of brain-organoid neuronal connectivity has not been studied systematically yet. In this study, we apply high-density micro-electrode arrays (MEAs) to record from developing mouse cerebral organoids and characterize their spontaneous neuronal activity. Results provide first evidence on the potential of MEAs as a platform to study the role of spontaneous neuronal activity during brain organoid development and formation of functional microcircuits. Close https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00066/event_abstract doi:10.3389/conf.fncel.2018.38.00066 Close
	Bartram, Julian; Schroter, Manuel; Ronchi, Silvia; Emmenegger, Vishalini; Muller, Jan; Hierlemann, Andreas Probing synaptic connectivity and function using high-density microelectrode arrays and whole-cell patch-clamp recordings Conference 11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting) Reutlingen, Germany, 2018. Abstract \| Links \| BibTeX \| Tags: HD-MEA @conference{Bartram2018b, title = {Probing synaptic connectivity and function using high-density microelectrode arrays and whole-cell patch-clamp recordings}, author = {Julian Bartram and Manuel Schroter and Silvia Ronchi and Vishalini Emmenegger and Jan Muller and Andreas Hierlemann}, url = {https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00085/5473/MEA_Meeting_2018_%7C_11th_International_Meeting_on_Substrate_Integrated_Microelectrode_Arrays/all_events/event_abstract}, doi = {10.3389/conf.fncel.2018.38.00085}, year = {2018}, date = {2018-07-04}, address = {Reutlingen, Germany}, organization = {11th International Meeting on Substrate Integrated Microelectrode Arrays (MEA Meeting)}, abstract = {Synaptic efficacy and synapse number of monosynaptic connections between neurons are often regulated by the spiking activity of the respective pre- and postsynaptic cell. Progress towards a better understanding of the rules and mechanisms that underlie such modifications has been limited due to the difficulties associated with simultaneously studying plasticity at multiple synaptic inputs. Here, we provide a solution to this problem by combining cutting-edge high-density microelectrode array (HD-MEA) technology with the patch-clamp technique. While the latter allows for accurate measurement of postsynaptic currents or potentials, evoked by individual synaptic activation, the HD-MEA technology provides large-scale information about unit activity and allows for selective stimulation of neurons, including multiple presynaptic cells. The proposed approach has been applied to comprehensively examine forms of homeostatic plasticity – a collection of crucial processes acting at different temporal scales in order to stabilize neuronal firing rates. We report on a characterization of classic synaptic scaling operating in mature cortical networks and propose a novel model for the study of homeostatic plasticity during natural network states. }, keywords = {HD-MEA}, pubstate = {published}, tppubtype = {conference} } Close Synaptic efficacy and synapse number of monosynaptic connections between neurons are often regulated by the spiking activity of the respective pre- and postsynaptic cell. Progress towards a better understanding of the rules and mechanisms that underlie such modifications has been limited due to the difficulties associated with simultaneously studying plasticity at multiple synaptic inputs. Here, we provide a solution to this problem by combining cutting-edge high-density microelectrode array (HD-MEA) technology with the patch-clamp technique. While the latter allows for accurate measurement of postsynaptic currents or potentials, evoked by individual synaptic activation, the HD-MEA technology provides large-scale information about unit activity and allows for selective stimulation of neurons, including multiple presynaptic cells. The proposed approach has been applied to comprehensively examine forms of homeostatic plasticity – a collection of crucial processes acting at different temporal scales in order to stabilize neuronal firing rates. We report on a characterization of classic synaptic scaling operating in mature cortical networks and propose a novel model for the study of homeostatic plasticity during natural network states. Close https://www.frontiersin.org/10.3389/conf.fncel.2018.38.00085/5473/MEA_Meeting_20[...] doi:10.3389/conf.fncel.2018.38.00085 Close
	da Drinnenberg Antonia; Franke, Felix; Morikawa Rei Jüttner; Hillier Daniel; Hantz Peter; Hierlemann Andreas; Azeredo Silveira Rava; Roska Botond K; How diverse retinal functions arise from feedback at the first visual synapse Journal Article Neuron, 99 (1), pp. 117-134, 2018. Abstract \| Links \| BibTeX \| Tags: Retina @article{Drinnenberg2018, title = {How diverse retinal functions arise from feedback at the first visual synapse}, author = {Drinnenberg, Antonia; Franke, Felix; Morikawa, Rei K; Jüttner; Hillier, Daniel; Hantz, Peter; Hierlemann, Andreas; Azeredo da Silveira, Rava; Roska, Botond}, url = {https://www.cell.com/neuron/fulltext/S0896-6273(18)30469-0}, doi = {10.1016/j.neuron.2018.06.001}, year = {2018}, date = {2018-06-21}, journal = {Neuron}, volume = {99}, number = {1}, pages = {117-134}, abstract = {Many brain regions contain local interneurons of distinct types. How does an interneuron type contribute to the input-output transformations of a given brain region? We addressed this question in the mouse retina by chemogenetically perturbing horizontal cells, an interneuron type providing feedback at the first visual synapse, while monitoring the light-driven spiking activity in thousands of ganglion cells, the retinal output neurons. We uncovered six reversible perturbation-induced effects in the response dynamics and response range of ganglion cells. The effects were enhancing or suppressive, occurred in different response epochs, and depended on the ganglion cell type. A computational model of the retinal circuitry reproduced all perturbation-induced effects and led us to assign specific functions to horizontal cells with respect to different ganglion cell types. Our combined experimental and theoretical work reveals how a single interneuron type can differentially shape the dynamical properties of distinct output channels of a brain region.}, keywords = {Retina}, pubstate = {published}, tppubtype = {article} } Close Many brain regions contain local interneurons of distinct types. How does an interneuron type contribute to the input-output transformations of a given brain region? We addressed this question in the mouse retina by chemogenetically perturbing horizontal cells, an interneuron type providing feedback at the first visual synapse, while monitoring the light-driven spiking activity in thousands of ganglion cells, the retinal output neurons. We uncovered six reversible perturbation-induced effects in the response dynamics and response range of ganglion cells. The effects were enhancing or suppressive, occurred in different response epochs, and depended on the ganglion cell type. A computational model of the retinal circuitry reproduced all perturbation-induced effects and led us to assign specific functions to horizontal cells with respect to different ganglion cell types. Our combined experimental and theoretical work reveals how a single interneuron type can differentially shape the dynamical properties of distinct output channels of a brain region. Close https://www.cell.com/neuron/fulltext/S0896-6273(18)30469-0 doi:10.1016/j.neuron.2018.06.001 Close
	Fiscella, Michele; Leary, Noelle; Ronchi, Silvia; Hierlemann, Andreas Electrophysiological phenotype characterization of human iPSC-derived dopaminergic neuronal lines by means of high-resolution microelelectrode arrays Conference W-2151 , International Society for Stem Cell Research (ISSCR) Annual Meeting Melbourne, Australia, 2018. Abstract \| Links \| BibTeX \| Tags: HD-MEA, IPSC @conference{Fiscella2018b, title = {Electrophysiological phenotype characterization of human iPSC-derived dopaminergic neuronal lines by means of high-resolution microelelectrode arrays}, author = {Michele Fiscella and Noelle Leary and Silvia Ronchi and Andreas Hierlemann }, url = {http://www.isscr.org/docs/default-source/2018-melbourne-ann-mtng/66670-isscr-abstracts_with-links.pdf?sfvrsn=4&utm_source=ISSCR-Informz&utm_medium=email&utm_campaign=default}, year = {2018}, date = {2018-06-20}, volume = {W-2151}, address = {Melbourne, Australia}, organization = {International Society for Stem Cell Research (ISSCR) Annual Meeting}, abstract = {High-resolution-microelectrode-array (MEA) technology enables to study neuronal dynamics at different scales, ranging from axonal physiology to network connectivity (Müller et. al, Lab on a Chip, 2015). We have used this MEA technology to characterize and compare the electrical phenotypes of commercially available human dopaminergic neurons (iCell DopaNeurons, MyCell DopaNeurons A53T α-synuclein, Cellular Dynamics International, Madison, WI, US). Furthermore, we have studied the effect of human astrocytes (iCell Astrocytes, Cellular Dynamics International, Madison, WI, US) on neural culture development. Astrocyte/neuron co- cultures showed higher signal amplitudes and higher firing rates than neural cultures without astrocytes. Adding astrocytes to neural cultures changed the whole culture morphology by promoting cell clustering. Interestingly, astrocyte/neuron co-cultures showed a lower sample-to-sample variability across multiple MEA recordings compared to neural cultures without astrocytes. We compared action potential propagation velocities along axons between dopaminergic A53T α-synuclein neurons and the wild-type isogenic control cell line. We found that in both, wild-type and disease model neurons, axonal action potential propagation velocities were lower than in rat primary cortical neurons. Furthermore, we found different axonal action potential velocity development profiles of A53T α-synuclein dopaminergic neurons and the wild-type counterpart. Finally, we were able to precisely evoke action potentials in individual single human neurons by subcellular- resolution electrical stimulation. High-resolution MEA systems enable to access novel electrophysiological parameters of iPSC-derived neurons, which can be potentially used as biomarkers for phenotype screening and drug testing.}, keywords = {HD-MEA, IPSC}, pubstate = {published}, tppubtype = {conference} } Close High-resolution-microelectrode-array (MEA) technology enables to study neuronal dynamics at different scales, ranging from axonal physiology to network connectivity (Müller et. al, Lab on a Chip, 2015). We have used this MEA technology to characterize and compare the electrical phenotypes of commercially available human dopaminergic neurons (iCell DopaNeurons, MyCell DopaNeurons A53T α-synuclein, Cellular Dynamics International, Madison, WI, US). Furthermore, we have studied the effect of human astrocytes (iCell Astrocytes, Cellular Dynamics International, Madison, WI, US) on neural culture development. Astrocyte/neuron co- cultures showed higher signal amplitudes and higher firing rates than neural cultures without astrocytes. Adding astrocytes to neural cultures changed the whole culture morphology by promoting cell clustering. Interestingly, astrocyte/neuron co-cultures showed a lower sample-to-sample variability across multiple MEA recordings compared to neural cultures without astrocytes. We compared action potential propagation velocities along axons between dopaminergic A53T α-synuclein neurons and the wild-type isogenic control cell line. We found that in both, wild-type and disease model neurons, axonal action potential propagation velocities were lower than in rat primary cortical neurons. Furthermore, we found different axonal action potential velocity development profiles of A53T α-synuclein dopaminergic neurons and the wild-type counterpart. Finally, we were able to precisely evoke action potentials in individual single human neurons by subcellular- resolution electrical stimulation. High-resolution MEA systems enable to access novel electrophysiological parameters of iPSC-derived neurons, which can be potentially used as biomarkers for phenotype screening and drug testing. Close http://www.isscr.org/docs/default-source/2018-melbourne-ann-mtng/66670-isscr-abs[...] 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
	Viswam, Vijay; Obien, Marie Engelene J; Frey, Urs; Franke, Felix; Hierlemann, Andreas Acquisition of Bioelectrical Signals with Small Electrodes Conference 2017 IEEE Biomedical Circuits and Systems Conference (BioCAS) Turin, Italy, 2017. Abstract \| Links \| BibTeX \| Tags: Electrodes @conference{Viswam2017, title = {Acquisition of Bioelectrical Signals with Small Electrodes}, author = {Vijay Viswam and Marie Engelene J. Obien and Urs Frey and Felix Franke and Andreas Hierlemann}, url = {https://ieeexplore.ieee.org/document/8325216}, doi = {10.1109/BIOCAS.2017.8325216}, year = {2017}, date = {2017-10-19}, address = {Turin, Italy}, organization = {2017 IEEE Biomedical Circuits and Systems Conference (BioCAS)}, abstract = {Although the mechanisms of recording bioelectrical signals from different types of electrogenic cells (neurons, cardiac cells etc.) by means of planar metal electrodes have been extensively studied, the recording characteristics and conditions for very small electrode sizes are not yet established. Here, we present a combined experimental and computational approach to elucidate, how the electrode size influences the recorded signals, and how inherent properties of the electrode, such as impedance, noise, and transmission characteristics shape the signal. We demonstrate that good quality recordings can be achieved with electrode diameters of less than 10 μm, provided that impedance reduction measures have been implemented and provided that a set of requirements for signal amplification has been met.}, keywords = {Electrodes}, pubstate = {published}, tppubtype = {conference} } Close Although the mechanisms of recording bioelectrical signals from different types of electrogenic cells (neurons, cardiac cells etc.) by means of planar metal electrodes have been extensively studied, the recording characteristics and conditions for very small electrode sizes are not yet established. Here, we present a combined experimental and computational approach to elucidate, how the electrode size influences the recorded signals, and how inherent properties of the electrode, such as impedance, noise, and transmission characteristics shape the signal. We demonstrate that good quality recordings can be achieved with electrode diameters of less than 10 μm, provided that impedance reduction measures have been implemented and provided that a set of requirements for signal amplification has been met. Close https://ieeexplore.ieee.org/document/8325216 doi:10.1109/BIOCAS.2017.8325216 Close
	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
	Tajima Satohiro; Mita, Takeshi; Bakkum Douglas Takahashi Hirokazu; Toyoizumi Taro J; Locally embedded presages of global network bursts Journal Article National Academy of Sciences, pp. 1-6, 2017, ISSN: 0027-8424. Abstract \| Links \| BibTeX \| Tags: Neuronal Networks @article{Tajima2017, title = {Locally embedded presages of global network bursts}, author = {Tajima, Satohiro; Mita, Takeshi; Bakkum, Douglas J; Takahashi, Hirokazu; Toyoizumi, Taro}, editor = {Sejnowski, Terrence J}, url = {http://www.pnas.org/content/114/36/9517}, doi = {10.1073/pnas.1705981114 }, issn = {0027-8424}, year = {2017}, date = {2017-08-18}, journal = {National Academy of Sciences}, pages = {1-6}, abstract = {Spontaneous, synchronous bursting of neural population is a widely observed phenomenon in nervous networks, which is considered important for functions and dysfunctions of the brain. However, how the global synchrony across a large number of neurons emerges from an initially nonbursting network state is not fully understood. In this study, we develop a state-space reconstruction method combined with high-resolution recordings of cultured neurons. This method extracts deterministic signatures of upcoming global bursts in “local” dynamics of individual neurons during nonbursting periods. We find that local information within a single-cell time series can compare with or even outperform the global mean-field activity for predicting future global bursts. Moreover, the intercell variability in the burst predictability is found to reflect the network structure realized in the nonbursting periods. These findings suggest that deterministic local dynamics can predict seemingly stochastic global events in self-organized networks, implying the potential applications of the present methodology to detecting locally concentrated early warnings of spontaneous seizure occurrence in the brain.}, keywords = {Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close Spontaneous, synchronous bursting of neural population is a widely observed phenomenon in nervous networks, which is considered important for functions and dysfunctions of the brain. However, how the global synchrony across a large number of neurons emerges from an initially nonbursting network state is not fully understood. In this study, we develop a state-space reconstruction method combined with high-resolution recordings of cultured neurons. This method extracts deterministic signatures of upcoming global bursts in “local” dynamics of individual neurons during nonbursting periods. We find that local information within a single-cell time series can compare with or even outperform the global mean-field activity for predicting future global bursts. Moreover, the intercell variability in the burst predictability is found to reflect the network structure realized in the nonbursting periods. These findings suggest that deterministic local dynamics can predict seemingly stochastic global events in self-organized networks, implying the potential applications of the present methodology to detecting locally concentrated early warnings of spontaneous seizure occurrence in the brain. Close http://www.pnas.org/content/114/36/9517 doi:10.1073/pnas.1705981114 Close
	Shein-Idelson, Mark; Pammer, Lorenz; Hemberger, Mike; Laurent, Gilles Large-scale mapping of cortical synaptic projections with extracellular electrode arrays Journal Article Nature Methods, 14 (9), pp. 882–889, 2017, ISSN: 1548-7091. Abstract \| Links \| BibTeX \| Tags: Brain Slice, MaxOne, Neuronal Networks @article{Shein-Idelson2017, title = {Large-scale mapping of cortical synaptic projections with extracellular electrode arrays}, author = {Mark Shein-Idelson and Lorenz Pammer and Mike Hemberger and Gilles Laurent}, url = {http://www.nature.com/doifinder/10.1038/nmeth.4393}, doi = {10.1038/nmeth.4393}, issn = {1548-7091}, year = {2017}, date = {2017-08-14}, journal = {Nature Methods}, volume = {14}, number = {9}, pages = {882--889}, abstract = {Understanding circuit computation in the nervous system requires sampling activity over large neural populations and maximizing the number of features that can be extracted. By combining planar arrays of extracellular electrodes with the three-layered cortex of turtles, we show that synaptic signals induced along individual axons as well as action potentials can be easily captured. Two types of information can be extracted from these signals, the neuronal subtype (inhibitory or excitatory)—whose identification is more reliable than with traditional measures such as action potential width—and a (partial) spatial map of functional axonal projections from individual neurons. Because our approach is algorithmic, it can be carried out in parallel on hundreds of simultaneously recorded neurons. Combining our approach with soma triangulation, we reveal an axonal projection bias among a population of pyramidal neurons in turtle cortex and confirm this bias through anatomical reconstructions.}, keywords = {Brain Slice, MaxOne, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close Understanding circuit computation in the nervous system requires sampling activity over large neural populations and maximizing the number of features that can be extracted. By combining planar arrays of extracellular electrodes with the three-layered cortex of turtles, we show that synaptic signals induced along individual axons as well as action potentials can be easily captured. Two types of information can be extracted from these signals, the neuronal subtype (inhibitory or excitatory)—whose identification is more reliable than with traditional measures such as action potential width—and a (partial) spatial map of functional axonal projections from individual neurons. Because our approach is algorithmic, it can be carried out in parallel on hundreds of simultaneously recorded neurons. Combining our approach with soma triangulation, we reveal an axonal projection bias among a population of pyramidal neurons in turtle cortex and confirm this bias through anatomical reconstructions. Close http://www.nature.com/doifinder/10.1038/nmeth.4393 doi:10.1038/nmeth.4393 Close
	Obien, Marie Engelene J; Zorzi, Giulio; Hierlemann, Andreas Mapping neuron cluster development based on axonal action potential propagation Conference The 40th Annual Meeting of the Japan Neuroscience Society Chiba, Japan, 2017. BibTeX \| Tags: Action Potential, Neuronal Networks @conference{Obien2017, title = {Mapping neuron cluster development based on axonal action potential propagation}, author = {Marie Engelene J. Obien and Giulio Zorzi and Andreas Hierlemann}, year = {2017}, date = {2017-07-20}, address = {Chiba, Japan}, organization = {The 40th Annual Meeting of the Japan Neuroscience Society}, keywords = {Action Potential, Neuronal Networks}, pubstate = {published}, tppubtype = {conference} } Close
	Diggelmann, Roland; Fiscella, Michele; Hierlemann, Andreas; Franke, Felix Pre-whitening as a means to improve dimensionality reduction and simplify clustering in spike-sorters for multi-electrode recordings Conference 26th Annual Computational Neuroscience Meeting (CNS2017) Antwerp, Belgium , 2017. Abstract \| Links \| BibTeX \| Tags: Spike Sorting @conference{Diggelmann2017, title = {Pre-whitening as a means to improve dimensionality reduction and simplify clustering in spike-sorters for multi-electrode recordings}, author = {Roland Diggelmann and Michele Fiscella and Andreas Hierlemann and Felix Franke}, url = {https://bmcneurosci.biomedcentral.com/articles/10.1186/s12868-017-0371-2}, year = {2017}, date = {2017-07-15}, address = {Antwerp, Belgium }, organization = {26th Annual Computational Neuroscience Meeting (CNS2017)}, abstract = {Spike sorting is the process to extract single neuronal activity from extracellular recordings. It makes use of the fact that spikes from a single neuron feature highly similar waveforms, whereas spikes from different neurons have different waveforms. Clustering algorithms are used to find groups of similar spikes that putatively originated from the same neuron. However, since spike waveforms especially in multi-electrode recordings can have a high dimensionality, their dimensionality needs to be reduced before clustering. Principal component analysis (PCA) is one of the most commonly employed dimensionality reduction methods for this purpose [1]. It reduces the dimensions to those where the variance of the data was highest, presumably those along which the waveforms of separate neurons differ most strongly, However, if the noise is not uniform in all dimensions, high variability can also mean high noise, which would render a dimension useless for discrimination. We, therefore, propose an additional pre-whitening step before PCA and discuss two beneficial effects on the subsequent clustering. We illustrate these effects by using spikes from retinal ganglion cells recorded with high-density multi-electrode arrays (HD-MEA).}, keywords = {Spike Sorting}, pubstate = {published}, tppubtype = {conference} } Close Spike sorting is the process to extract single neuronal activity from extracellular recordings. It makes use of the fact that spikes from a single neuron feature highly similar waveforms, whereas spikes from different neurons have different waveforms. Clustering algorithms are used to find groups of similar spikes that putatively originated from the same neuron. However, since spike waveforms especially in multi-electrode recordings can have a high dimensionality, their dimensionality needs to be reduced before clustering. Principal component analysis (PCA) is one of the most commonly employed dimensionality reduction methods for this purpose [1]. It reduces the dimensions to those where the variance of the data was highest, presumably those along which the waveforms of separate neurons differ most strongly, However, if the noise is not uniform in all dimensions, high variability can also mean high noise, which would render a dimension useless for discrimination. We, therefore, propose an additional pre-whitening step before PCA and discuss two beneficial effects on the subsequent clustering. We illustrate these effects by using spikes from retinal ganglion cells recorded with high-density multi-electrode arrays (HD-MEA). Close https://bmcneurosci.biomedcentral.com/articles/10.1186/s12868-017-0371-2 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
	Obien, Marie Engelene J; Muller, Jan; Boos, Julia Alicia; Bounik, Raziyeh; Fiscella, Michele; Hierlemann, Andreas High-resolution Functional Imaging of Cardiomyocytes Derived from Embryonic Stem Cell Spheroids Conference International Society for Stem Cell Research (ISSCR) Boston, MA, USA, 2017. Links \| BibTeX \| Tags: Cardiomyocytes, HD-MEA @conference{Obien2017b, title = {High-resolution Functional Imaging of Cardiomyocytes Derived from Embryonic Stem Cell Spheroids}, author = {Marie Engelene J. Obien and Jan Muller and Julia Alicia Boos and Raziyeh Bounik and Michele Fiscella and Andreas Hierlemann}, url = {http://www.isscr.org/docs/default-source/am17/64553-isscr-abstracts-proof-3-w-cover.pdf?sfvrsn=2}, year = {2017}, date = {2017-06-14}, address = {Boston, MA, USA}, organization = {International Society for Stem Cell Research (ISSCR) }, keywords = {Cardiomyocytes, HD-MEA}, pubstate = {published}, tppubtype = {conference} } Close http://www.isscr.org/docs/default-source/am17/64553-isscr-abstracts-proof-3-w-co[...] Close
	Fiscella, Michele; Muller, Jan; Hierlemann, Andreas High-resolution Microelectrode Array Platform for Biomarker Discovery and Novel Functional Assays in Human iPSC-derived Neurons Conference International Society for Stem Cell Research (ISSCR) Meeting Boston, MA, USA, 2017. Links \| BibTeX \| Tags: HD-MEA @conference{Fiscella2017, title = {High-resolution Microelectrode Array Platform for Biomarker Discovery and Novel Functional Assays in Human iPSC-derived Neurons}, author = {Michele Fiscella and Jan Muller and Andreas Hierlemann}, url = {http://www.isscr.org/docs/default-source/am17/64553-isscr-abstracts-proof-3-w-cover.pdf?sfvrsn=2}, year = {2017}, date = {2017-06-14}, address = {Boston, MA, USA}, organization = {International Society for Stem Cell Research (ISSCR) Meeting}, keywords = {HD-MEA}, pubstate = {published}, tppubtype = {conference} } Close http://www.isscr.org/docs/default-source/am17/64553-isscr-abstracts-proof-3-w-co[...] Close
	Frey, Urs; Obien, Marie Engelene J; Muller, Jan; Hierlemann, Andreas Technology Trends and Commercialization of High-density Microelectrode Arrays for Advanced In-vitro Electrophysiology Conference IEEE International Symposium on Circuits and Systems (ISCAS Baltimore, MD, USA, 2017, ISSN: 2379-447X. Abstract \| Links \| BibTeX \| Tags: HD-MEA, In-Vitro @conference{Frey2017, title = {Technology Trends and Commercialization of High-density Microelectrode Arrays for Advanced In-vitro Electrophysiology}, author = {Urs Frey and Marie Engelene J. Obien and Jan Muller and Andreas Hierlemann}, url = {https://ieeexplore.ieee.org/document/8050215/}, doi = {10.1109/ISCAS.2017.8050215}, issn = {2379-447X}, year = {2017}, date = {2017-05-28}, address = {Baltimore, MD, USA}, organization = {IEEE International Symposium on Circuits and Systems (ISCAS}, abstract = {Microelectrode arrays (MEAs) enable fast and high-throughput readout of cell's electrical signals. MEAs are currently used for phenotype characterization and drug toxicity/efficacy testing with iPSC-derived neurons and cardiomyocytes. A key advantage of MEAs is the capability to record and stimulate individual neurons at multiple sites simultaneously. We will present ongoing advancements of MEA technology, with a focus on achieving higher quality recordings by means of monolithic co-integration of circuitry on chip by using CMOS technology [1]. Such high-density MEAs with more than 3000 electrodes per mm2 are a suitable tool for capturing neuronal activity across various scales, including axons, somas, dendrites, entire neurons, and networks.}, keywords = {HD-MEA, In-Vitro}, pubstate = {published}, tppubtype = {conference} } Close Microelectrode arrays (MEAs) enable fast and high-throughput readout of cell's electrical signals. MEAs are currently used for phenotype characterization and drug toxicity/efficacy testing with iPSC-derived neurons and cardiomyocytes. A key advantage of MEAs is the capability to record and stimulate individual neurons at multiple sites simultaneously. We will present ongoing advancements of MEA technology, with a focus on achieving higher quality recordings by means of monolithic co-integration of circuitry on chip by using CMOS technology [1]. Such high-density MEAs with more than 3000 electrodes per mm2 are a suitable tool for capturing neuronal activity across various scales, including axons, somas, dendrites, entire neurons, and networks. Close https://ieeexplore.ieee.org/document/8050215/ doi:10.1109/ISCAS.2017.8050215 Close
	Hillier, Daniel; Fiscella, Michele; Drinnenberg, Antonia; Trenholm, Stuart; Rompani, Santiago B; Raics, Zoltan; Katona, Gergely; Jüttner, Josephine; Hierlemann, Andreas; Rozsa, Balazs; Roska, Botond Causal evidence for retina-dependent and -independent visual motion computations in mouse cortex Journal Article Nature Neuroscience, 20 (7), pp. 960–968, 2017, ISSN: 1097-6256. Abstract \| Links \| BibTeX \| Tags: MaxOne, Retina @article{Hillier2017, title = {Causal evidence for retina-dependent and -independent visual motion computations in mouse cortex}, author = {Daniel Hillier and Michele Fiscella and Antonia Drinnenberg and Stuart Trenholm and Santiago B Rompani and Zoltan Raics and Gergely Katona and Josephine Jüttner and Andreas Hierlemann and Balazs Rozsa and Botond Roska}, url = {http://www.nature.com/doifinder/10.1038/nn.4566}, doi = {10.1038/nn.4566}, issn = {1097-6256}, year = {2017}, date = {2017-05-22}, journal = {Nature Neuroscience}, volume = {20}, number = {7}, pages = {960--968}, abstract = {How neuronal computations in the sensory periphery contribute to computations in the cortex is not well understood. We examined this question in the context of visual-motion processing in the retina and primary visual cortex (V1) of mice. We disrupted retinal direction selectivity, either exclusively along the horizontal axis using FRMD7 mutants or along all directions by ablating starburst amacrine cells, and monitored neuronal activity in layer 2/3 of V1 during stimulation with visual motion. In control mice, we found an over-representation of cortical cells preferring posterior visual motion, the dominant motion direction an animal experiences when it moves forward. In mice with disrupted retinal direction selectivity, the over-representation of posterior-motion-preferring cortical cells disappeared, and their responses at higher stimulus speeds were reduced. This work reveals the existence of two functionally distinct, sensory-periphery-dependent and -independent computations of visual motion in the cortex.}, keywords = {MaxOne, Retina}, pubstate = {published}, tppubtype = {article} } Close How neuronal computations in the sensory periphery contribute to computations in the cortex is not well understood. We examined this question in the context of visual-motion processing in the retina and primary visual cortex (V1) of mice. We disrupted retinal direction selectivity, either exclusively along the horizontal axis using FRMD7 mutants or along all directions by ablating starburst amacrine cells, and monitored neuronal activity in layer 2/3 of V1 during stimulation with visual motion. In control mice, we found an over-representation of cortical cells preferring posterior visual motion, the dominant motion direction an animal experiences when it moves forward. In mice with disrupted retinal direction selectivity, the over-representation of posterior-motion-preferring cortical cells disappeared, and their responses at higher stimulus speeds were reduced. This work reveals the existence of two functionally distinct, sensory-periphery-dependent and -independent computations of visual motion in the cortex. Close http://www.nature.com/doifinder/10.1038/nn.4566 doi:10.1038/nn.4566 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
2016
	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, 2016, 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 = {2016}, date = {2016-11-30}, 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
	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
	Lewandowska, Marta K; Radivojevic, Milos; Jäckel, David; Müller, Jan; Hierlemann, Andreas Cortical axons, isolated in channels, display activity-dependent signal modulation as a result of targeted stimulation Journal Article Frontiers in Neuroscience, 10 , pp. 83, 2016, ISSN: 1662453X. Abstract \| Links \| BibTeX \| Tags: MaxOne, Neuronal Networks, u-Tunnels @article{Lewandowska2016, title = {Cortical axons, isolated in channels, display activity-dependent signal modulation as a result of targeted stimulation}, author = {Marta K Lewandowska and Milos Radivojevic and David Jäckel and Jan Müller and Andreas Hierlemann}, url = {https://www.frontiersin.org/articles/10.3389/fnins.2016.00083/full}, doi = {10.3389/fnins.2016.00083}, issn = {1662453X}, year = {2016}, date = {2016-03-07}, journal = {Frontiers in Neuroscience}, volume = {10}, pages = {83}, abstract = {Mammalian cortical axons are extremely thin processes that are difficult to study as a result of their small diameter: they are too narrow to patch while intact, and super-resolution microscopy is needed to resolve single axons. We present a method for studying axonal physiology by pairing a high-density microelectrode array with a microfluidic axonal isolation device, and use it to study activity-dependent modulation of axonal signal propagation evoked by stimulation near the soma. Up to three axonal branches from a single neuron, isolated in different channels, were recorded from simultaneously using 10-20 electrodes per channel. The axonal channels amplified spikes such that propagations of individual signals along tens of electrodes could easily be discerned with high signal to noise. Stimulation from 10 up to 160 Hz demonstrated similar qualitative results from all of the cells studied: extracellular action potential characteristics changed drastically in response to stimulation. Spike height decreased, spike width increased, and latency increased, as a result of reduced propagation velocity, as the number of stimulations and the stimulation frequencies increased. Quantitatively, the strength of these changes manifested itself differently in cells at different frequencies of stimulation. Some cells' signal fidelity fell to 80% already at 10 Hz, while others maintained 80% signal fidelity at 80 Hz. Differences in modulation by axonal branches of the same cell were also seen for different stimulation frequencies, starting at 10 Hz. Potassium ion concentration changes altered the behavior of the cells causing propagation failures at lower concentrations and improving signal fidelity at higher concentrations.}, keywords = {MaxOne, Neuronal Networks, u-Tunnels}, pubstate = {published}, tppubtype = {article} } Close Mammalian cortical axons are extremely thin processes that are difficult to study as a result of their small diameter: they are too narrow to patch while intact, and super-resolution microscopy is needed to resolve single axons. We present a method for studying axonal physiology by pairing a high-density microelectrode array with a microfluidic axonal isolation device, and use it to study activity-dependent modulation of axonal signal propagation evoked by stimulation near the soma. Up to three axonal branches from a single neuron, isolated in different channels, were recorded from simultaneously using 10-20 electrodes per channel. The axonal channels amplified spikes such that propagations of individual signals along tens of electrodes could easily be discerned with high signal to noise. Stimulation from 10 up to 160 Hz demonstrated similar qualitative results from all of the cells studied: extracellular action potential characteristics changed drastically in response to stimulation. Spike height decreased, spike width increased, and latency increased, as a result of reduced propagation velocity, as the number of stimulations and the stimulation frequencies increased. Quantitatively, the strength of these changes manifested itself differently in cells at different frequencies of stimulation. Some cells' signal fidelity fell to 80% already at 10 Hz, while others maintained 80% signal fidelity at 80 Hz. Differences in modulation by axonal branches of the same cell were also seen for different stimulation frequencies, starting at 10 Hz. Potassium ion concentration changes altered the behavior of the cells causing propagation failures at lower concentrations and improving signal fidelity at higher concentrations. Close https://www.frontiersin.org/articles/10.3389/fnins.2016.00083/full doi:10.3389/fnins.2016.00083 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
	Müller, Jan; Ballini, Marco; Livi, Paolo; Chen, Yihui; Radivojevic, Milos; Shadmani, Amir; Viswam, Vijay; Jones, Ian L; Fiscella, Michele; Diggelmann, Roland; Stettler, Alexander; Frey, Urs; Bakkum, Douglas J; Hierlemann, Andreas High-resolution CMOS MEA platform to study neurons at subcellular, cellular, and network levels Journal Article Lab Chip, 15 (13), pp. 2767-2780, 2015, ISSN: 1473-0197. Abstract \| Links \| BibTeX \| Tags: MaxOne, Neuronal Networks @article{Muller2015, title = {High-resolution CMOS MEA platform to study neurons at subcellular, cellular, and network levels}, author = {Jan Müller and Marco Ballini and Paolo Livi and Yihui Chen and Milos Radivojevic and Amir Shadmani and Vijay Viswam and Ian L Jones and Michele Fiscella and Roland Diggelmann and Alexander Stettler and Urs Frey and Douglas J Bakkum and Andreas Hierlemann}, url = {http://pubs.rsc.org/en/Content/ArticleLanding/2015/LC/C5LC00133A#!divAbstract}, doi = {10.1039/C5LC00133A}, issn = {1473-0197}, year = {2015}, date = {2015-07-07}, journal = {Lab Chip}, volume = {15}, number = {13}, pages = {2767-2780}, publisher = {Royal Society of Chemistry}, abstract = {Studies on information processing and learning properties of neuronal networks would benefit from simultaneous and parallel access to the activity of a large fraction of all neurons in such networks. Here, we present a CMOS-based device, capable of simultaneously recording the electrical activity of over a thousand cells in in vitro neuronal networks. The device provides sufficiently high spatiotemporal resolution to enable, at the same time, access to neuronal preparations on subcellular, cellular, and network level. The key feature is a rapidly reconfigurable array of 26 400 microelectrodes arranged at low pitch (17.5 um) within a large overall sensing area (3.85 × 2.10 mm2). An arbitrary subset of the electrodes can be simultaneously connected to 1024 low-noise readout channels as well as 32 stimulation units. Each electrode or electrode subset can be used to electrically stimulate or record the signals of virtually any neuron on the array. We demonstrate the applicability and potential of this device for various different experimental paradigms: large-scale recordings from whole networks of neurons as well as investigations of axonal properties of individual neurons.}, keywords = {MaxOne, Neuronal Networks}, pubstate = {published}, tppubtype = {article} } Close Studies on information processing and learning properties of neuronal networks would benefit from simultaneous and parallel access to the activity of a large fraction of all neurons in such networks. Here, we present a CMOS-based device, capable of simultaneously recording the electrical activity of over a thousand cells in in vitro neuronal networks. The device provides sufficiently high spatiotemporal resolution to enable, at the same time, access to neuronal preparations on subcellular, cellular, and network level. The key feature is a rapidly reconfigurable array of 26 400 microelectrodes arranged at low pitch (17.5 um) within a large overall sensing area (3.85 × 2.10 mm2). An arbitrary subset of the electrodes can be simultaneously connected to 1024 low-noise readout channels as well as 32 stimulation units. Each electrode or electrode subset can be used to electrically stimulate or record the signals of virtually any neuron on the array. We demonstrate the applicability and potential of this device for various different experimental paradigms: large-scale recordings from whole networks of neurons as well as investigations of axonal properties of individual neurons. Close http://pubs.rsc.org/en/Content/ArticleLanding/2015/LC/C5LC00133A#!divAbstract doi:10.1039/C5LC00133A Close
	Krol, Jacek; Krol, Ilona; Alvarez, Claudia Patricia Patino; Fiscella, Michele; Hierlemann, Andreas; Roska, Botond; Filipowicz, Witold A network comprising short and long noncoding RNAs and RNA helicase controls mouse retina architecture. Journal Article Nature Communications, 6 , pp. 7305, 2015, ISSN: 2041-1723. Abstract \| Links \| BibTeX \| Tags: MaxOne, Retina @article{Krol2015, title = {A network comprising short and long noncoding RNAs and RNA helicase controls mouse retina architecture.}, author = {Jacek Krol and Ilona Krol and Claudia Patricia Patino Alvarez and Michele Fiscella and Andreas Hierlemann and Botond Roska and Witold Filipowicz}, url = {https://www.nature.com/articles/ncomms8305}, doi = {10.1038/ncomms8305}, issn = {2041-1723}, year = {2015}, date = {2015-06-04}, journal = {Nature Communications}, volume = {6}, pages = {7305}, publisher = {Nature Publishing Group}, abstract = {Brain regions, such as the cortex and retina, are composed of layers of uniform thickness. The molecular mechanism that controls this uniformity is not well understood. Here we show that during mouse postnatal development the timed expression of Rncr4, a retina-specific long noncoding RNA, regulates the similarly timed processing of pri-miR-183/96/182, which is repressed at an earlier developmental stage by RNA helicase Ddx3x. Shifting the timing of mature miR-183/96/182 accumulation or interfering with Ddx3x expression leads to the disorganization of retinal architecture, with the photoreceptor layer being most affected. We identify Crb1, a component of the adhesion belt between glial and photoreceptor cells, as a link between Rncr4-regulated miRNA metabolism and uniform retina layering. Our results suggest that the precise timing of glia-neuron interaction controlled by noncoding RNAs and Ddx3x is important for the even distribution of cells across layers.}, keywords = {MaxOne, Retina}, pubstate = {published}, tppubtype = {article} } Close Brain regions, such as the cortex and retina, are composed of layers of uniform thickness. The molecular mechanism that controls this uniformity is not well understood. Here we show that during mouse postnatal development the timed expression of Rncr4, a retina-specific long noncoding RNA, regulates the similarly timed processing of pri-miR-183/96/182, which is repressed at an earlier developmental stage by RNA helicase Ddx3x. Shifting the timing of mature miR-183/96/182 accumulation or interfering with Ddx3x expression leads to the disorganization of retinal architecture, with the photoreceptor layer being most affected. We identify Crb1, a component of the adhesion belt between glial and photoreceptor cells, as a link between Rncr4-regulated miRNA metabolism and uniform retina layering. Our results suggest that the precise timing of glia-neuron interaction controlled by noncoding RNAs and Ddx3x is important for the even distribution of cells across layers. Close https://www.nature.com/articles/ncomms8305 doi:10.1038/ncomms8305 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

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Publications

Publications

Selected Publications

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

Revealing Neuronal Function through Microelectrode Array Recordings

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

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

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

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

All Publications

2019

2018

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2016

2015