UCLA

It has recently been demonstrated by several researchers that ultrasound at intensities well below the commonly accepted threshold for effect on humans is potentially capable of reversibly modulating neuronal circuits and function. However, several critical barriers exist to translating these theories and techniques to the clinic as a non-invasive transcranial therapeutic or neural research tool.

The primary goal of thesis is to enable detailed exploration of the relationship between the nature of the ultrasonic stimulus and a neuromodulatory outcome by exploring the hypothesis that low intensity ultrasound can be discretely targeted to neural structures to induce neuromodulation. This work is undertaken with the ultimate goal of advancing safe, controllable ultrasonic neuromodulation as a treatment for human neurologic diseases through an exploration of targeting - the engineering challenge of applying known quantities of ultrasound to known locations.

An experimental assay of the effect of hypothalamic sonication in the G�ttingen minipig was developed to explore targeted neuromodulation in the brain of a larger animal model. A transducer, coupling system, and surgical procedure were developed that allowed for spatially accurate stereotactic transcranial sonication of deep-brain structures with known acoustic intensities. A pilot study assaying the effect of ultrasonic stimulation targeted to the hypothalamus in the minipig yielded preliminary evidence that a set of ultrasonic pulsing parameters exist that can induce a statistically significant rise in heart rate (>5%) coincident with ultrasonic stimulation.

Targeting was also explored through the development of an invasive neurostimulation paradigm. Novel <1.8 mm diameter low frequency ultrasonic microtransducers were developed, micro fabricated, and characterized for this effort. The targeting potential for this paradigm was demonstrated in a feasibility study in the rat. Targeting was further explored through the development of an algorithm for effectively sampling the ultrasonic parameter space by nesting the prime drivers of bioeffects into a matched-pair sampling framework of acoustic parameters.

With these results, this work provides an engineering foundation for future systematic studies of ultrasonic neuromodulatory effects. Through the exploration of targeting and parameter selection enabled by this work, rigorous assays for ultrasonic neuromodulation can now be conducted.