The overarching aim of this project is to study the cellular bases of modulation of neuronal activity using ultrasound. Ultrasound is now becoming recognized as an important new modality for noninvasively modulating neuronal functions in the brain because: (a) a focused beam can be applied noninvasively from outside the head to any region of the brain, even deep in the brain within a very small region (1-3 mm in Full Width Half Maximum (FWHM) for a 1 Megahertz (MHz) ultrasound beam); and because (b) Ultrasound can be used to safely modulate neuronal activity within the FDA safety limit. This project will examine two mechanisms of neuromodulation that are still hardly investigated, the modulation of membrane capacitance Cm and conductance gm associated with the lipid bilayer of the cell membranes, in an isolated giant axon of the crayfish. This project has broad impact in three areas: (1) It will pave a way to study the biophysics of the ionic channels and lipid membranes in the MHz domain, thereby providing insights into the kinetics of single ion channels that open and close in a millisecond scale; (2) It will provide the foundation for using ultrasound as a new modality for tomographic neuroimaging with a millimeter and a millisecond resolution that is just beginning to be investigated by this group and perhaps others; and (3) It will provide a specific new mechanism for opening the blood-brain barrier with important implications in drug delivery.
Ultrasound (US) can modulate Cm by either the cavitation or radiation force. When a pressure wave of US hits the membrane, its cavitation force is thought to expand, oscillate or collapse gas bodies in the tissue or solution around it, deforming the bilayer geometry in synchrony with the period of ultrasound and thereby modulating Cm. Ultrasound can also alter Cm by mechanically moving the membrane due to the radiation force caused by spatial gradients in acoustic intensity. Empirically, the radiation force can produce strong clearly detectable capacitive current across a synthesized lipid bilayer at the onset and offset of a train of ultrasound pulses. The PIs will study the modulation of Cm by the cavitation force. This mechanism has not been studied experimentally in biological preparations, in comparison to the effect of the radiation force on Cm, even though simulation studies imply that this type of modulation should produce very strong intracellular currents.
