PROJECT SUMMARY In this Bioengineering Research project, we propose to develop a novel technique for frequency-domain near- infrared spectroscopy (FD-NIRS) that aims to achieve selective sensitivity to deeper tissue in non-invasive diffuse optical spectroscopy and imaging. A technique that features a stronger sensitivity to deeper tissue relative to superficial tissue can have a broad impact on non-invasive optical diagnostics and monitoring and is especially important in cerebral oximetry and functional brain imaging. The proposed technique is based on the new concept of phase dual-slopes (this is the phase of the modulated optical signal measured in FD-NIRS), which requires a minimum of two light sources and two optical detectors placed on the tissue according to a special arrangement. In addition to achieving selective sensitivity to deeper tissue, phase dual slopes are weakly sensitive to instrumental drifts and motion artifacts (except spikes), which is a highly desirable property for robust measurements. First, we will use diffusion theory and Monte Carlo simulations to identify source/detector geometrical arrangements and intensity modulation frequencies that optimize performance of the phase dual-slope for a variety of heterogeneous layered media. Second, we will implement optimal phase dual-slope conditions with a commercial FD-NIRS instrument to demonstrate effectiveness on tissue-like phantoms, and we will design special source-detector arrays for imaging based on the Moore-Penrose pseudoinverse of the Jacobian matrix for phase dual-slope measurements. Third, we will design and build a dedicated compact, wearable, fiber-less, and cost-effective FD-NIRS device for further broadening the applicability of the phase dual-slope method to freely moving subjects in everyday conditions, and for point-of- care applications. Fourth, we will perform human studies for technical performance tests (in skeletal muscle during vascular occlusions) and to demonstrate the effectiveness of the phase dual-slope method for functional brain imaging (in the prefrontal cortex during cognitive activation). In particular, the latter study will elucidate the relative blood flow/blood volume contributions to cortical hemodynamics and will allow for dual-task measurements in subjects performing cognitive tasks while walking. The broad objective of this project is to advance the field of diffuse optical measurements of biological tissue by developing special techniques for collection and analysis of FD-NIRS data to enhance the quality, reliability, and information content of non- invasive NIRS in research and clinical applications.

PROJECT NARRATIVE Accurate non-invasive optical measurements of cerebral hemodynamics require suppression of confounding contributions from superficial tissue (scalp, skull, etc.) and motion artifacts. This project aims to develop an optical technique that minimizes these confounding contributions, thus paving the way for a more effective assessment of brain function and neurovascular pathologies. A wearable device, also developed in this project, will further extend this optical technique to point-of-care diagnostics.