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

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

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

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

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

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

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

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

@article{Takahashi2017,
title = {Development of neural population activity toward self-organized criticality},
author = {Yuichiro Yada and Takeshi Mita and Akihiro Sanada and Ryuichi Yano and Ryohei Kanzaki and Douglas J Bakkum and Andreas Hierlemann and Hirokazu Takahashi},
url = {http://www.sciencedirect.com/science/article/pii/S0306452216306522},
doi = {10.1016/j.neuroscience.2016.11.031},
issn = {0306-4522},
year = {2017},
date = {2017-02-20},
journal = {Neuroscience},
volume = {343},
pages = {55-65},
abstract = {Self-organized criticality (SoC), a spontaneous dynamic state established and maintained in networks of moderate complexity, is a universal characteristic of neural systems. Such systems produce cascades of spontaneous activity that are typically characterized by power-law distributions and rich, stable spatiotemporal patterns (i.e., neuronal avalanches). Since the dynamics of the critical state confer advantages in information processing within neuronal networks, it is of great interest to determine how criticality emerges during development. One possible mechanism is developmental, and includes axonal elongation during synaptogenesis and subsequent synaptic pruning in combination with the maturation of GABAergic inhibition (i.e., the integration then fragmentation process). Because experimental evidence for this mechanism remains inconclusive, we studied the developmental variation of neuronal avalanches in dissociated cortical neurons using high-density complementary metal-oxide semiconductor (CMOS) microelectrode arrays (MEAs). The spontaneous activities of nine cultures were monitored using CMOS MEAs from 4 to 30 days in vitro (DIV) at single-cell spatial resolution. While cells were immature, cultures demonstrated random-like patterns of activity and an exponential avalanche size distribution; this distribution was followed by a bimodal distribution, and finally a power-law-like distribution. The bimodal distribution was associated with a large-scale avalanche with a homogeneous spatiotemporal pattern, while the subsequent power-law distribution was associated with diverse patterns. These results suggest that the SoC emerges through a two-step process: the integration process accompanying the characteristic large-scale avalanche and the fragmentation process associated with diverse middle-size avalanches.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

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

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

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

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

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

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