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As synchronized activity is associated with basic brain functions and pathological states, spike train synchrony has become an important measure to analyze experimental neuronal data. Many measures of spike train synchrony have been proposed, but there is no gold standard allowing for comparison of results from different experiments. This work aims to provide guidance on which synchrony measure is best suited to quantify the effect of epileptiform-inducing substances (e.g., bicuculline, BIC) in in vitro neuronal spike train data. Spike train data from recordings are likely to suffer from erroneous spike detection, such as missed spikes (false negative) or noise (false positive). Therefore, different timescale-dependent (cross-correlation, mutual information, spike time tiling coefficient) and timescale-independent (Spike-contrast, phase synchronization (PS), A-SPIKE-synchronization, A-ISI-distance, ARI-SPIKE-distance) synchrony measures were compared in terms of their robustness to erroneous spike trains. For this purpose, erroneous spike trains were generated by randomly adding (false positive) or deleting (false negative) spikes (in silico manipulated data) from experimental data. In addition, experimental data were analyzed using different spike detection threshold factors in order to confirm the robustness of the synchrony measures. All experimental data were recorded from cortical neuronal networks on microelectrode array chips, which show epileptiform activity induced by the substance BIC. As a result of the in silico manipulated data, Spike-contrast was the only measure that was robust to false-negative as well as false-positive spikes. Analyzing the experimental data set revealed that all measures were able to capture the effect of BIC in a statistically significant way, with Spike-contrast showing the highest statistical significance even at low spike detection thresholds. In summary, we suggest using Spike contrast to complement established synchrony measures because it is timescale independent and robust to erroneous spike trains.
Background: Connectivity is a relevant parameter for the information flow within neuronal networks. Network connectivity can be reconstructed from recorded spike train data. Various methods have been developed to estimate connectivity from spike trains. New method: In this work, a novel effective connectivity estimation algorithm called Total Spiking Probability Edges (TSPE) is proposed and evaluated. First, a cross-correlation between pairs of spike trains is calculated. Second, to distinguish between excitatory and inhibitory connections, edge filters are applied on the resulting cross-correlogram. Results: TSPE was evaluated with large scale in silico networks and enables almost perfect reconstructions (true positive rate of approx. 99% at a false positive rate of 1% for low density random networks) depending on the network topology and the spike train duration. A distinction between excitatory and inhibitory connections was possible. TSPE is computational effective and takes less than 3 min on a high-performance computer to estimate the connectivity of an 1 h dataset of 1000 spike trains. Comparison of existing methods: TSPE was compared with connectivity estimation algorithms like Transfer Entropy based methods, Filtered and Normalized Cross-Correlation Histogram and Normalized Cross-Correlation. In all test cases, TSPE outperformed the compared methods in the connectivity reconstruction accuracy. Conclusions: The results show that the accuracy of functional connectivity estimation of large scale neuronal networks has been enhanced by TSPE compared to state of the art methods. Furthermore, TSPE enables the classification of excitatory and inhibitory synaptic effects.
Applying technologies of additive manufacturing to the field of tissue engineering created a pioneering new approach to model complex cell systems artificially. Regarding its huge potential, bioprinting is still in its infancies and many questions are still unanswered. To address this issue, an extrusion-based bioprinting (EBB) process was used to deposit human embryonic kidney (HEK) cells in a defined pattern. It was shown that the bioprinted construct featured a high degree in viability reaching up to 77% 10 days after printing (DAP). This work displays a proof of principle for a controlled cell formation which shall later be applied to in vitro drug screening tests using various types of cells.
Transparent poly(3,4-ethylenedioxythiophene)-based microelectrodes for extracellular recording
(2018)
It is well known that at the interface between neuronal tissue and recording electrode low electrical impedance is required. However, if simultaneous optical detection or stimulation is an issue, good optical transmittance of the electrode material is desirable as well. State-of-the-art titanium nitride electrodes provide superior low impedance compared to gold or iridium, but are nontransparent. Transparent electrode materials like the transparent conducting oxide, indium tin oxide (ITO), or graphene offer high light transmittance (>80%) but reveal relatively high impedance. In this paper, the authors propose the conducting polymer poly(3,4-ethylenedioxythiophene) with the counter ion NO−3 as the electrode material for low impedance and good optical transmittance properties. The polymer is electrochemically deposited onto ITO improving the relatively high impedance of ITO. This multilayer electrode allows not only for electrophysiological recordings of cardiomyocytes but also for monitoring of cell contraction under the microscope. Electrochemical impedance spectroscopy and action potential recordings reveal that the new transparent electrodes are a good compromise in terms of low impedance and transparency if deposition parameters are optimized.
High LET radiation shows no major cellular and functional effects on primary cardiomyocytes in vitro
(2018)
It is well known that ionizing radiation causes adverse effects on various mammalian tissues. However, there is little information on the biological effects of heavy ion radiation on the heart. In order to fill this gap, we systematically examined DNA-damage induction and repair, as well as proliferation and apoptosis in avian cardiomyocyte cultures irradiated with heavy ions such as titanium and iron, relevant for manned space-flight, and carbon ions, as used for radiotherapy. Further, and to our knowledge for the first time, we analyzed the effect of heavy ion radiation on the electrophysiology of primary cardiomyocytes derived from chicken embryos using the non-invasive microelectrode array (MEA) technology. As electrophysiological endpoints beat rate and field action potential duration were analyzed.
The cultures clearly exhibited the capacity to repair induced DNA damage almost completely within 24 h, even at doses of 7 Gy, and almost completely recovered from radiation-induced changes in proliferative behavior. Interestingly, no significant effects on apoptosis could be detected. Especially the functionality of primary cardiac cells exhibited a surprisingly high robustness against heavy ion radiation, even at doses of up to 7 Gy. In contrast to our previous study with X-rays the beat rate remained more or less unaffected after heavy ion radiation, independently of beam quality. The only change we could observe was an increase of the field action potential duration of up to 30% after titanium irradiation, diminishing within the following three days. This potentially pathological observation may be an indication that heavy ion irradiation at high doses could bear a long-term risk for cardiovascular disease induction.
Terrestrial Trunked Radio (TETRA) is a worldwide common mobile communication standard, used by authorities and organizations with security tasks. Previous studies reported on health effects of TETRA, with focus on the specific pulse frequency of 17.64 Hz, which affects calcium efflux in neuronal cells. Likewise among others, it was reported that TETRA affects heart rate variability, neurophysiology and leads to headaches. In contrast, other studies conclude that TETRA does not affect calcium efflux of cells and has no effect on people's health.
In the present study we examine whether TETRA short- and long-term exposure could affect the electrophysiology of neuronal in vitro networks. Experiments were performed with a carrier frequency of 395 MHz, a pulse frequency of 17.64 Hz and a differential quaternary phase-shift keying (π/4 DQPSK) modulation. Specific absorption rates (SAR) of 1.17 W/kg and 2.21 W/kg were applied.
In conclusion, the present results do not indicate any effect of TETRA exposure on electrophysiology of neuronal in vitro networks, neither for short-term nor long-term exposure. This applies to the examined parameters spike rate, burst rate, burst duration and network synchrony.
Microelectrode array (MEA) technology in combination with three-dimensional (3D) neuronal cell models derived from human embryonic stem cells (hESC) provide an excellent tool for neurotoxicity screening. Yet, there are significant challenges in terms of data processing and analysis, since neuronal signals have very small amplitudes and the 3D structure enhances the level of background noise. Thus, neuronal signal analysis requires the application of highly sophisticated algorithms. In this study, we present a new approach optimized for the detection of spikes recorded from 3D neurospheres (NS) with a very low signal-to-noise ratio. This was achieved by extending simple threshold-based spike detection utilizing a highly sensitive algorithm named SWTTEO. This analysis procedure was applied to data obtained from hESC-derived NS grown on MEA chips. Specifically, we examined changes in the activity pattern occurring within the first ten days of electrical activity. We further analyzed the response of NS to the GABA receptor antagonist bicuculline. With this new algorithm method we obtained more reliable results compared to the simple threshold-based spike detection.
Various studies have shown that two dimensional (2D) neuronal cell cultures does not recapitulate structure and physiology of three-dimensional (3D) in vivo tissues. These findings are of paramount importance for drug screening, since the response to neurotoxicological substances may differ for 2D und 3D cell culture models. To address this topic, we present human embryonic stem cell (hESC) derived neurospheres (NS) coupled onto microelectrode array (MEA) chips as a model system that includes a 3D NS as well as an outgrowing 2D monolayer allowing direct comparison of functionality within one culture. Preliminary results revealed an enhanced functional reactions of 3D NS to GABA receptor antagonist bicuculline compared to the 2D domain. Thus we have the first evidence that hESC derived NS are a promising model system for neurotoxicity testing enabling a direct comparison between functionality of neurons grown in 2D or 3D.