Development of an Experimental Platform to Enable Ultrasound Neuromodulation Studies

Focused ultrasound (FUS) neuromodulation is the delivery of concentrated mechanical energy into central nervous tissue at low intensity (a few W per cm^2; about as intense as imaging ultrasound, and not sufficiently intense to cause heating) with the goal of eliciting a functional change. It is of interest to applied and clinical scientists as a prospective non-invasive therapeutic intervention; it is also applicable to basic scientists as a tool for in vivo brain mapping. This work details the development of a device and accompanying system that enables the study of ultrasound-mediated neuromodulation in brain tissue samples in a setting with concurrent electrophysiology. We use a novel ultrasound focusing technique based on principles of acoustic reflection, and the first research chapter discusses the development and integration of this focusing technique. To develop and refine our design, I used finite-element modeling and iterative computer optimization techniques. The concordance of these in silico techniques with reality was verified with prototypes and hydrophone acoustic field measurements. Subsequently, several production-quality ultrasound units were produced to the specifications determined by modeling; these units exhibited performance improvements based on the results from testing prototypes, and they were characterized in terms of efficiency, electrical impedance, and ultrasonic pressure field shape. We used two independent methods to verify the absolute acoustic intensity output by our device: radiation-force absorber measurements in conjunction with wide-field hydrophone scans, and then later a calibrated hydrophone. The second research chapter of this manuscript describes the application of our system to neuroscientific experiments: I detail how we obtained early data pertaining to the ability of pulsed FUS to modulate field potential activity in acute animal brain slices. We observed an intensity-dependent modulation effect in a majority of slices tested (>50%, n=44); however, this effect was determined to be dominated by a confound and unlikely to be physiological. This course of study explored and evaluated a novel technique for obtaining an ultrasound focus; it also yielded a system that enables further experiments into interactions between FUS and brain tissue. This manuscript, the devices resulting from the work, and the documentation included in the appendices will enable continued investigations into ultrasound neuromodulation at the University of Calgary.

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