A whole-brain ultrasonic neural stimulation and photoacoustic recording system in behaving animals

Project Summary: Decoding the electrical and chemical signals in neural circuits is essential to understand the communication between different brain regions and how these neural networks give rise to a particular function at the level of the whole organism. Therefore, recording or modulating neural activity with high spatiotemporal resolution is necessary. Ideally it is desired to achieve this noninvasively for long-term translation of these technologies to behaving animals and eventually to humans. The general tradeoff in neural stimulation and recording technologies is between spatial resolution and the size of the region covered by the recording/stimulation sites. Noninvasive technologies offer stimulation and recording capability in a large brain area, but suffer from low spatial and temporal resolution and limited depth. Invasive technologies provide improved spatial and temporal resolution to interrogate the activity of a single neuron, but fail to scale beyond tens or hundreds of neurons. In this project, we aim to develop a tool that is capable of ultrasonic neural stimulation in a 3D volume by dynamic beamforming and real-time recording of hemodynamic activity in response to stimulation by volumetric photoacoustic imaging. The described technology will equip the neuroscience community with a research tool to further explore the emerging field of ultrasonic neural stimulation and to monitor metabolic/hemodynamic responses in awake/behaving animals with real-time photoacoustic imaging. Using high-frequency ultrasound enables micrometer-millisecond spatiotemporal resolution for stimulation. Using a fast-repeating laser source, the same can be achieved for monitoring the activity. Use of a 2D transducer array enables combination of ultrasound neuromodulation and photoacoustic imaging in the same device because a target site in a 3D volume can be stimulated and hemodynamic response can be monitored by photoacoustic imaging at all other points in the overall 3D volume. 2D transducer arrays that are commonly available can stimulate a point on a plane and reconstruct the image of the same plane only, which is very restricting. The specific objective of this exploratory study is to develop a 10-MHz, 16x16-element, 2D CMUT array with integrated electronics and optics that is capable of ultrasonic neural stimulation in a 20x20x20-mm3 volume by dynamic transmit beamforming and real-time recording of hemodynamic activity in response to stimulation by volumetric photoacoustic imaging. To fulfill this objective, we have identified the following specific aims: Specific Aim 1: Design and implement a 10-MHz, 16x16-element 2D wideband (>100% fractional band- width, i.e. from 5 MHz to 15 MHz) CMUT array with through-wafer interconnects. Specific Aim 2: Design and implement a pixel-pitch-matched integrated circuit with 16x16 channels capable of phased array transmission for ultrasound neural stimulation and receiving from all elements in a time-multiplexed fashion for photoacoustic imaging. Specific Aim 3: Validate the prototype in-vivo in anesthetized and behaving animals.