Optical monitoring of brain activities is intrinsically associated with various operational advantages, including low-cost and portable noninvasive bedside continuous monitoring capabilities. While the preva- lent optical brain monitoring methods are based on measuring blood oxygenation level-dependent (BOLD) signals from blood absorption, optical methods measuring cerebral blood flow (CBF) from the decor- relation of coherent light when scattered by the blood flow may provide a promising alternative. CBF measurement has higher sensitivity to the brain and is complementary to BOLD signals. Their combi- nation can provide a more precise picture of neural activity and may be, for example, used to compute the metabolic oxygen uptake rate in the brain. Noninvasive CBF measurement is also instrumental for functional neuroimaging of the human brain for cerebrovascular health, cognitive aging, and neuroin- tensive care. However, the current optical CBF detection methods, such as diffusion correlation spec- troscopy (DCS), laser speckle-based imaging, and their variants, are prone to extracerebral contami- nation. They are limited in depth sensitivity relying on the distribution of the photon paths. For this R21 project, we propose to develop and evaluate a novel CBF measurement method, known as ultrasonic- tagged remote interferometric flowmetry (URIF), for the task of high sensitivity and selectivity brain activ- ity monitoring. URIF is substantially different from current optical CBF methods. Whereas current optical CBF methods measure an integrated signal from all optical paths in which the signal photons that have passed through the brain activity site are overwhelmed by non-signal photons that have not, URIF se- lects and coherently amplifies only the signal photons through ultrasonic tagging and heterodyne detec- tion. More importantly, with a novel theoretical and experimental framework, URIF can quantify the local CBF at the millimeter-size brain activity site at depths reaching one centimeter and beyond, removing ex- tracerebral contamination and significantly enhancing depth sensitivity, selectivity, and spatial resolution. Local absorption variation associated with hemodynamics can also be monitored simultaneously. We propose first to develop URIF using single-shot off-axis holography and then numerically and experimen- tally validate URIF on human brain phantoms. The performance metrics of URIF for measuring deep flow will be determined in terms of accuracy, sensitivity, and selectivity. If successful, the technology will pave a novel avenue for remote flowmetry of brain activity and fill a vital measurement gap that existing optical and non-optical methods have not been able to address.

This project proposes to develop and validate ultrasonic-tagged remote interferometric flowmetry for brain activity with single-shot off-axis holography. The outcome of this project is a noninvasive imaging platform for quantifying the local dynamics inside deep tissue through ultrasonic tagging. It will pave the way for highly selective and accurate recording of local CBF and absorption variation associated with brain activity in human brains with millimeter spatial resolution and at a depth of one centimeter and be- yond.