Spike-frequency dependent inhibition and excitation of neural activity by high-frequency ultrasound

Abstract

Prieto et al. describe how ultrasound can either inhibit or potentiate action potential firing in hippocampal pyramidal neurons and demonstrate that these effects can be explained by increased potassium conductance. ABSTRACTUltrasound can modulate action potential firing in vivo and in vitro, but the mechanistic basis of this phenomenon is not well understood. To address this problem, we used patch-clamp recording to quantify the effects of focused, high-frequency (43 MHz) ultrasound on evoked action potential firing in CA1 pyramidal neurons in acute rodent hippocampal brain slices. We find that ultrasound can either inhibit or potentiate firing in a spike-frequency-dependent manner: at low (nearthreshold) input currents and low firing frequencies, ultrasound inhibits firing, while at higher input currents and higher firing frequencies, ultrasound potentiates firing. The net result of these two competing effects is that ultrasound increases the threshold current for action potential firing, the slope of frequency-input curves, and the maximum firing frequency. In addition, ultrasound slightly hyperpolarizes the resting membrane potential, decreases action potential width, and increases the depth of the afterhyperpolarization. All of these results can be explained by the hypothesis that ultrasound activates a sustained potassium conductance. According to this hypothesis, increased outward potassium currents hyperpolarize the resting membrane potential and inhibit firing at near-threshold input currents, but potentiate firing in response to higher input currents by limiting inactivation of voltage-dependent sodium channels during the action potential. This latter effect is a consequence of faster action-potential repolarization, which limits inactivation of voltage-dependent sodium channels, and deeper (more negative) afterhyperpolarization, which increases the rate of recovery from inactivation. Based on these results we propose that ultrasound activates thermosensitive and mechanosensitive, voltage-insensitive two-poredomain potassium (K2P) channels, through heating or mechanical effects of acoustic radiation force. Finite-element modelling of the effects of ultrasound on brain tissue suggests that the effects of ultrasound on firing frequency are caused by a small (less than 2°C) increase in temperature, with possible additional contributions from mechanical effects. 93force produced by reflection of the acoustic wave at the interface between the solution and the air 94 above it (Duck, 1998)). The mound of fluid was then aligned in the x-y plane to the center of a 95 reticle in one eyepiece of the dissecting microscope, and, after adding additional ACSF and the 96 tissue sample to the chamber, the center of the reticle was aligned with the region of the tissue 97 targeted for patch-clamp recording. The ultrasound intensity (50 W/cm 2 ) is the spatial peak, pulse 98 average intensity for the free field. The interval between ultrasound applications was at least 12 99 seconds. 101Electrophysiology. Current clamp re...

Repetitive pulsed-wave ultrasound stimulation suppresses neural activity by modulating ambient GABA levels via effects on astrocytes

“…As reported in previous papers, the gigaohm seals required for patch-clamp often broke when ultrasound stimulation was applied during whole-cell recording (Tyler et al, 2008;Prieto et al, 2020;Duque et al, 2022). Furthermore, the cells themselves were sometimes ruptured by the ultrasound.…”

“…A solution to this is to use frequencies in the MHz range rather than the 500 kHz generally used for stimulation. So far, it has been possible to make recordings with 43 MHz stimulation under intense sound pressure (Prieto et al, 2018(Prieto et al, , 2020. In addition, recordings with 7 MHz, 0.5 MPa single-shot stimulation have been achieved (Duque et al, 2022).…”

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“…120,121 In more details, the inhibitory effects found to be associated with thermal effects of TUS seem to involve increased potassium channels conductance, which in turn, decrease resting membrane potential and neuronal firing. 122,123 Some thermo-sensitive potassium channel subtypes have been identified, i.e., TREK1,2, and K2P or TRAAK. All in all, there is increasing evidence supporting the role of the thermal effects in TUS induced neuronal inhibition, with maximal effects for temperature rise of + 0.5 °C.…”

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“…60,61 The proposed effects are thermal, mechanical due to the acoustic force, or cavitational, and depend on the ultrasound frequency and intensity. 62 Specificity of focused ultrasound can be further improved by utilizing piezoelectric particle transducers that generate current upon ultrasound stimulation and can thus modulate voltage-gated ion channels. 63 In a similar manner, magnetic particles in combination with alternating magnetic field can be used to stimulate excitable cells.…”