Abstract
Low-intensity ultrasonic waves can remotely and nondestructively excite central nervous system (CNS) neurons. While diverse applications for this effect are already emerging, the biophysical transduction mechanism underlying this excitation remains unclear. Recently, we suggested that ultrasound-induced intramembrane cavitation within the bilayer membrane could underlie the biomechanics of a range of observed acoustic bioeffects. In this paper, we show that, in CNS neurons, ultrasound-induced cavitation of these nanometric bilayer sonophores can induce a complex mechanoelectrical interplay leading to excitation, primarily through the effect of currents induced by membrane capacitance changes. Our model explains the basic features of CNS acoustostimulation and predicts how the experimentally observed efficacy of mouse motor cortical ultrasonic stimulation depends on stimulation parameters. These results support the hypothesis that neuronal intramembrane piezoelectricity underlies ultrasound-induced neurostimulation, and suggest that other interactions between the nervous system and pressure waves or perturbations could be explained by this new mode of biological piezoelectric transduction.
Highlights
Is ultrasound (US) widely used for imaging [1]; its interaction with biological tissues is known to induce a wide variety of nonthermal effects ranging from hemorrhage and necrosis [2] to more delicate manipulations of cells and their membranes such as permeability enhancement [3], angiogenesis induction [4,5,6], and increased gene transfection [7]
A final simulation study examined excitation by 0.5MHz US pulse trains for different intensities and duty cycle values. (Pulse-mode US is commonly used in applications in which it is desirable to avoid heating the tissue, including neural stimulation.) We have found that the action potentials (APs) excitation mechanism for pulsed excitation is generally the same as for the CW mode (Fig. 2)
Such an understanding can guide the development of future therapeutic applications of the only technology currently capable of targeted noninvasive brain stimulation
Summary
Is ultrasound (US) widely used for imaging [1]; its interaction with biological tissues is known to induce a wide variety of nonthermal effects ranging from hemorrhage and necrosis [2] to more delicate manipulations of cells and their membranes such as permeability enhancement [3], angiogenesis induction [4,5,6], and increased gene transfection [7] Both classical and recent studies have demonstrated that US can interact with the physiology of excitable tissues, inducing the generation of action potentials (APs) [8,9,10,11,12,13,14,15,16,17,18], suppression of nerve conduction [19,20,21], as well as more subtle changes in excitability [22,23,24]. This mechanoelectrical coupling is shown to induce displacement currents that excite action potentials through an indirect mechanism, whose features explain the requirement for long ultrasonic stimulation pulses [12,16,18] and predict the experimentally observed efficacy of ultrasonic stimulation in mouse motor cortex [18]
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