Dissertation/Thesis Abstract

Optogenetic vs. Electrical Stimulation of Human Cardiomyocytes: Modeling Insights
by Williams, John Connor, M.S., State University of New York at Stony Brook, 2015, 43; 1595003
Abstract (Summary)

Optogenetics provides an alternative to electrical stimulation to manipulate membrane voltage and trigger or modify action potentials in excitable cells. We compare biophysically and energetically the cellular responses to direct electrical current injection vs. optical stimulation mediated by genetically-expressed light-sensitive ion channels, e.g. Channelrhodopsin-2 (ChR2). Using a computational model of ChR2(H134R mutant), we show that both stimulation modalities produce similar in morphology action potentials in human cardiomyocytes, and that electrical and optical excitability vary with cell type in a similar fashion. However, whereas the strength-duration curves for electrical excitation in ventricular and atrial cardiomyocytes closely follow the theoretical exponential relationship for an equivalent RC circuit, the respective optical strength-duration curves significantly deviate, exhibiting higher nonlinearity. We trace the origin of this deviation to the waveform of the excitatory current –a non-rectangular self-terminating inward current produced in optical stimulation due to ChR2 kinetics and voltage-dependent rectification. Using a unifying “charge” measure to compare energy needed for electrical and optical stimulation, we reveal that direct electrical current injection (rectangular pulse) is more efficient at short pulses, whereas voltage-mediated negative feedback leads to self-termination of ChR2 current and renders optical stimulation more efficient for long low-intensity pulses. This applies to cardiomyocytes but not to neuronal cells (with much shorter action potentials). Furthermore, we demonstrate the cell-specific use of ChR2 current as a unique modulator of intrinsic activity, allowing for optical control of action potential duration in atrial and, to a lesser degree, in ventricular myocytes. For self-oscillatory cells, such as Purkinje, constant light at extremely low irradiance can be used for fine control of oscillatory frequency, whereas constant electrical stimulation is not feasible due to electrochemical limitations. Our analysis offers insights for designing future new energy-efficient stimulation strategies in heart or brain.

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Indexing (document details)
Advisor: Entcheva, Emilia, Kamoua, Ridha
Commitee: Westerfeld, David
School: State University of New York at Stony Brook
Department: Electrical Engineering
School Location: United States -- New York
Source: MAI 54/06M(E), Masters Abstracts International
Subjects: Biomedical engineering, Medicine, Physiology
Keywords: Bioelectricity, Cardiac, Electrophysiology, Optical, Optogenetics, Simulations
Publication Number: 1595003
ISBN: 978-1-321-92875-4
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