Tveito, A. | bioRxiv Science

bioRxiv2018

Inversion and computational maturation of drug response using human stem cell derived cardiomyocytes in microphysiological systems

While cardiomyocytes differentiated from human induced pluripotent stems cells (hiPSCs) hold great promise for drug screening, the electrophys-iological properties of these cells can be variable and immature, producing results that are significantly different from their human adult counterparts. Here, we describe a computational framework to address this limitation, and show how in silico methods, applied to measurements on immature cardiomyocytes, can be used to both identify drug action and to predict its effect in mature cells. Our synthetic and experimental results indicate that optically obtained waveforms of voltage and calcium from microphysiological systems can be inverted into information on drug ion channel blockage, and then, through assuming functional invariance of proteins during maturation, this data can be used to predict drug induced changes in mature ventricular cells. Together, this pipeline of measurements and computational analysis could significantly improve the ability of hiPSC derived cardiomycocytes to predict dangerous drug side effects.

biophysics↗

bioRxiv2018

Can the presence of neural probes be neglected in computational modeling of extracellular potentials?

AbstractO_ST_ABSObjectiveC_ST_ABSMechanistic modeling of neurons is an essential component of computational neuroscience that enables scientists to simulate, explain, and explore neural activity. The conventional approach to simulation of extracellular neural recordings first computes transmembrane currents using the cable equation and then sums their contribution to model the extracellular potential. This two-step approach relies on the assumption that the extracellular space is an infinite and homogeneous conductive medium, while measurements are performed using neural probes. The main purpose of this paper is to assess to what extent the presence of the neural probes of varying shape and size impacts the extracellular field and how to correct for them.\n\nApproachWe apply a detailed modeling framework allowing explicit representation of the neuron and the probe to study the effect of the probes and thereby estimate the effect of ignoring it. We use meshes with simplified neurons and different types of probe and compare the extracellular action potentials with and without the probe in the extracellular space. We then compare various solutions to account for the probes presence and introduce an efficient probe correction method to include the probe effect in modeling of extracellular potentials.\n\nMain resultsOur computations show that microwires hardly influence the extracellular electric field and their effect can therefore be ignored. In contrast, Multi-Electrode Arrays (MEAs) significantly affect the extracellular field by magnifying the recorded potential. While MEAs behave similarly to infinite insulated planes, we find that their effect strongly depends on the neuron-probe alignment and probe orientation.\n\nSignificanceIgnoring the probe effect might be deleterious in some applications, such as neural localization and parameterization of neural models from extracellular recordings. Moreover, the presence of the probe can improve the interpretation of extracellular recordings, by providing a more accurate estimation of the extracellular potential generated by neuronal models.

bioengineering↗