High-Frequency Electrical Stimulation of Cardiac Cells and Application to Artifact Reduction

Abstract

A novel modality for the electrical stimulation of cardiac cells is described. The technique is based on HF stimulation-burst of HF (1-25 kHz) biphasic square waves-to depolarize the cells and trigger action potentials (APs). HF stimulation was demonstrated in HL-1 cardiomyocyte cultures using microelectrode arrays, and the underlying mechanisms were investigated using single-cell model simulations. Current thresholds for HF stimulation increased at higher frequencies or shorter burst durations, and were typically higher than thresholds for single biphasic pulses. Nonetheless, owing to the decreasing impedance of metal electrodes with increasing frequencies, HF bursts resulted in reduced electrode voltages (up to four fold). Such lowered potentials might be beneficial in reducing the probability of irreversible electrochemical reactions and tissue damage, especially for long-term stimulation. More significantly, stimulation at frequencies higher than the upper limit of the AP power spectrum allows effective artifact reduction by low-pass filtering. Shaping of the burst envelope provides further reduction of the remaining artifact. This ability to decouple extracellular stimulation and recording in the frequency domain allowed detection of APs during stimulation-something previously not achievable to the best of our knowledge.

Spatiotemporally Controlled Cardiac Conduction Block Using High-Frequency Electrical Stimulation

“…High-frequency stimulation provides further advantages for integration in electrophysiology systems. By using stimuli of higher frequencies than the measured potentials (typical upper limit of 1–2 kHz), the artifacts caused by this type of stimulation can be filtered out, thus allowing simultaneous recording of the tissue activity during stimulation [20] . This allows for real-time confirmation of the effectiveness of the inhibition, for instance, or for application in cardiac mapping, effectively alleviating the need for further optical measurement methods (Ca 2+ or voltage-sensitive fluorescent dyes).…”

“…This allows for real-time confirmation of the effectiveness of the inhibition, for instance, or for application in cardiac mapping, effectively alleviating the need for further optical measurement methods (Ca 2+ or voltage-sensitive fluorescent dyes). In addition, the lower impedance of metal electrodes at high frequencies means that for a similar stimulation current, the electrode voltage will be lower for a higher frequency stimulus, thereby reducing irreversible chemical reactions and tissue damage [20] , [21] .…”

“…While AC stimuli of low frequencies (<20 Hz) are able to depolarize the cell on their first phase, they generally fail to do so at higher frequencies due to the lower charge delivery per phase. At these higher frequencies, another study by the authors [20] suggests that stimulation of cells is based on an asymmetrical response of the membrane to AC signals (primarily from the Na + and K + channels), leading to an integration of sub-threshold phases until the depolarization threshold is reached ( Gildemeister effect ) [15] , [16] , [21] , [25] – [27] . Such integration was previously demonstrated for neurons by Bromm et al [26] and Shoen et al [21] , with an inward rectification by Na + channels as the main underlying mechanism.…”

Fabrication of MEA‐based nanocavity sensor arrays for extracellular recording of action potentials

“…In principle, electrical extracellular recording and stimulation techniques with microelectrode arrays (MEAs) are well established [8][9][10][11][12][13][14][15][16][17][18][19]. Nevertheless, standard planar microelectrodes have some shortcomings regarding impedance and resolution of single cell measurements.…”

Multi-parametric cell profiling with a CMOS quad-modality cellular interfacing array for label-free fully automated drug screening

“…61 However, simultaneous electrical stimulations and extracellular potential recordings on the same cellular samples remain a major challenge in practice, since the stimulation artefacts often saturate the extracellular potential recording amplifiers. 62,63 The required voltage amplitude of electrical stimulation is typically between 0.1 V and 10 V for successful cell pacing, while the evoked extracellular potential amplitude is only around 100 μV. [17][18][19][20][21] Therefore, simultaneous electrical stimulations and potential recordings require >60 dB realtime broadband stimulation artefact cancellation.…”