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.
- Received 1 August 2013
DOI:https://doi.org/10.1103/PhysRevX.4.011004
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Published by the American Physical Society
Popular Summary
A noninvasive method that can assess region-specific brain functions and modify and control aberrant brain activities would be a dream come true for neuroscience and neuromedicine. That is why the recently observed ability of low-intensity, focused ultrasound waves to stimulate neurons in different areas of the brain, including the area controlling visual function, has caused a great deal of excitement. Until now, however, this phenomenon was as mysterious as it is exciting: The relevant scientific literature on it is empirical and the explanations speculative. Both qualitative and quantitative understanding that can guide future investigations is missing. In this paper, we present a new, concrete “neuronal bilayer sonophore” model that attempts to address this gap in understanding.
We have recently proposed a biomechanical membrane model that predicts the emergence of pulsating nanobubbles, induced by ultrasound, inside bilayer membranes of stimulated biological cells and, in particular, neurons. The current neuronal bilayer sonophore model takes the earlier model further with another conceptually new step: coupling the membrane mechanics, through a membrane-structure-dependent capacitance, to the generation of membrane action potentials, that is, neuronal firing. Using the fundamental Hodgkin-Huxley model for the emergence of such action potentials, we show that the pulsating membrane leaflets generate oscillations in the membrane potential that lead to a slow potential buildup across the membrane—until the buildup is discharged as an action potential. This new understanding explains, quantitatively, to a reasonably good degree, the slow effect of ultrasonic stimulation and provides a good fit to very recent in vivo measurements of muscle responses in mouse motor cortex to ultrasound stimulation.
These new concepts should facilitate the development of focused ultrasound stimulation—currently the only method that allows for controlled noninvasive stimulation of excitable tissues with millimeter spatial resolution essentially anywhere in the brain—and have various applications in the diagnosis and treatment of brain disorders.