DESCRIPTION (provided by applicant): All presently available neural stimulation methods are either invasive or can only be moderately localized, and a neurostimulation method that could overcome these limitations would be invaluable for brain circuit investigation. Neural stimulation with magnetic resonance guided high intensity focused ultrasound (MRgHIFU) is a promising technology that can noninvasively excite or inhibit neural activity in well-defined discrete volumes of the brain, subsequently enabling investigation of brain circuits with magnetic resonance imaging (MRI). We seek to explore this brain stimulation method in the somatosensory and visual systems of non- human primates with the goal of quantifying and expanding the capabilities of MRgHIFU as a tool for understanding neural circuits. The significance of this proposal results from the potential for ultrasound to be used as an investigative tool for neural stimulation that can address the shortcomings of other available methods. The mechanism of action of ultrasound on neurons suggests that different acoustic pulses can selectively activate neurons based on their ion channel types, allowing for cells to be differentially stimulated. In our preliminary work, we have developed methods for measuring and subsequently optimizing acoustic beams using MRI and designed a transducer array that is optimized for stimulation of the macaque cortex. We will integrate this into a high-field (7T) human magnet and implement novel methods for transcranially focusing a small burst of ultrasound within the macaque cortex in a controlled manner. With this technology in place, we will leverage our background in behavioral and neurophysiological measurements in macaques to quantify effects at the macro-, meso-, and microscale in behaving animals. We will then use blood oxygen level dependent functional MRI (BOLD fMRI) to map the S1 subregions of the brain during stimulation. Specifically, we will quantify the effect of acoustic parameters on BOLD fMRI and use ultrasound to inhibit or excite the skin tactile evoked response, while imaging the subsequent change in the BOLD signal. We will also use ultrasound to evoke activation patterns, and investigate the fine, middle, and long range circuits of the brain. Acoustic pulses will be designed to excite or inhibit neurons based on a newly validated model of the interaction of ultrasound with neurons. This model couples acoustically induced oscillation of cell membranes to the Hodgkin-Huxley model of action potential generation and may provide a method to differentially stimulate neurons based on their ion channels, which would be a very powerful and unprecedented neurostimulation technology. We propose simple experiments in a highly relevant animal that would test the utility of this model to design ultrasonic stimulation (either exciting or inhibiting) in localized regions and examine the BOLD fMRI signals resulting from such stimulation. The completion of these aims will expand the capabilities of MRgHIFU in conjunction with fMRI for investigating neural circuits, paving this way for this potentially important new approach to the assessment of brain function.

PUBLIC HEALTH RELEVANCE: An ultrasound transducer specifically designed for neurostimulation will be integrated into a high field (7T) human magnetic resonance imaging system and used to modulate the function of the well- studied visual and somatosensory systems of non-human primates. Using a mathematical model of ultrasonic interaction with neurons, we will develop acoustic pulses for transcranial stimulation that can stimulate or inhibit neuron activity. We will quantify the effects of these pulses on neural circuitry, validate the effects with neurophysiological measurements, and concurrently use functional MRI to non-invasively assess brain function at the circuit level.