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

Abstract

Ultrasound 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 (near-threshold) 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 after-hyperpolarization. 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) after-hyperpolarization, which increases the rate of recovery from inactivation. Based on these results, we propose that ultrasound activates thermosensitive and mechanosensitive two-pore-domain potassium (K2P) channels through heating or mechanical effects of acoustic radiation force. Finite-element modeling of the effects of ultrasound on brain tissue suggests that the effects of ultrasound on firing frequency are caused by a small (<2°C) increase in temperature, with possible additional contributions from mechanical effects.

The Inhibitory Thermal Effects of Focused Ultrasound on an Identified, Single Motoneuron

“…In Aplysia , heat-mediated (infrared) conduction block is greatly reduced by tetraethylammonium (TEA), a K V antagonist ( Ganguly et al, 2019a , b ). An additional primary or complementary source of [K + ] O may be via two-pore potassium channels, which are thermosensitive ( Schneider et al, 2014 ), and whose conductance increases on exposure to US ( Kubanek et al, 2016 ) by a reportedly thermal mechanism ( Prieto et al, 2020 ). Importantly, both classes of potassium channels are expressed ubiquitously by neurons, and a mechanism targeting these channels would circumvent the need to limit US-based neuromodulation therapies to classes of cells that express ion channels susceptible to US mechanical activation, including Piezo ( Prieto et al, 2018 ), TRP ( Yoo et al, 2020 ), and DEG/ENaC/ASIC ( Kubanek et al, 2018 ), or to introduce non-endogenous mechanosensitive ion channels in desired target tissue a la sonogenetics ( Ibsen et al, 2015 ).…”

High resolution ultrasonic neural modulation observed viain vivotwo-photon calcium imaging

“…Limited by the transducer bandwidth, the highest ultrasound frequency applied was 40 MHz 39 . To achieve even greater spatial resolution, higher frequencies (e.g.…”

Neuronal responses to focused ultrasound are gated by pre-stimulation brain rhythms

“…The dynamics of the sonicated region leading up to stimulation, especially neural oscillations, may exert a causal influence on the subsequent response to stimulation [38]. Indeed, there is in vitro evidence that the level of synaptic input exerts an influence on the neuronal response to ultrasound [39], and findings from functional magnetic resonance imaging (fMRI) suggest that neuromodulation outcome is dependent on whether the stimulated region is active [40]. To our knowledge, however, the influence of baseline neural oscillations on the subsequent neuronal response to ultrasonic neuromodulation has not yet been investigated.…”