@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 = {},
pubstate = {published},
tppubtype = {conference}
}

@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 = {},
pubstate = {published},
tppubtype = {conference}
}

@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 = {},
pubstate = {published},
tppubtype = {conference}
}

@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 = {},
pubstate = {published},
tppubtype = {conference}
}

@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 = {},
pubstate = {published},
tppubtype = {conference}
}

@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 = {},
pubstate = {published},
tppubtype = {conference}
}

@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 = {},
pubstate = {published},
tppubtype = {conference}
}

@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 = {},
pubstate = {published},
tppubtype = {conference}
}

@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 = {},
pubstate = {published},
tppubtype = {conference}
}

@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 = {},
pubstate = {published},
tppubtype = {conference}
}

@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 = {},
pubstate = {published},
tppubtype = {conference}
}

@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 = {},
pubstate = {published},
tppubtype = {conference}
}

@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 = {},
pubstate = {published},
tppubtype = {conference}
}

@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 = {},
pubstate = {published},
tppubtype = {conference}
}