Abstract. The tissue metabolic rate of oxygen consumption (tMRO 2 ) is a clinically relevant marker for a number of pathologies including cancer and arterial occlusive disease. We present and validate a noncontact method for quantitatively mapping tMRO 2 over a wide, scalable field of view at 16 frames∕s. We achieve this by developing a dual-wavelength, near-infrared coherent spatial frequency-domain imaging (cSFDI) system to calculate tissue optical properties (i.e., absorption, μ a , and reduced scattering, μ 0 s , parameters) as well as the speckle flow index (SFI) at every pixel. Images of tissue oxy-and deoxyhemoglobin concentration (½HbO 2 and [HHb]) are calculated from optical properties and combined with SFI to calculate tMRO 2 . We validate the system using a series of yeast-hemoglobin tissue-simulating phantoms and conduct in vivo tests in humans using arterial occlusions that demonstrate sensitivity to tissue metabolic oxygen debt and its repayment. Finally, we image the impact of cyanide exposure and toxicity reversal in an in vivo rabbit model showing clear instances of mitochondrial uncoupling and significantly diminished tMRO 2 . We conclude that dual-wavelength cSFDI provides rapid, quantitative, wide-field mapping of tMRO 2 that can reveal unique spatial and temporal dynamics relevant to tissue pathology and viability. © The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

In this work we introduce a modified form of laser speckle imaging (LSI) referred to as affixed transmission speckle analysis (ATSA) that uses a single coherent light source to probe two physiological signals: one related to pulsatile vascular expansion (classically known as the photoplethysmographic (PPG) waveform) and one related to pulsatile vascular blood flow (named here the speckle plethysmographic (SPG) waveform). The PPG signal is determined by recording intensity fluctuations, and the SPG signal is determined via the LSI dynamic light scattering technique. These two co-registered signals are obtained by transilluminating a single digit (e.g. finger) which produces quasi-periodic waveforms derived from the cardiac cycle. Because PPG and SPG waveforms probe vascular expansion and flow, respectively, in cm-thick tissue, these complementary phenomena are offset in time and have rich dynamic features. We characterize the timing offset and harmonic content of the waveforms in 16 human subjects and demonstrate physiologic relevance for assessing microvascular flow and resistance.

In this work we present and validate a wide-field method for the real-time mapping of tissue absorption, scattering and blood flow properties over wide regions of tissue (15 cm x 15 cm) with high temporal resolution (50 frames per second). We achieve this by applying Fourier Domain demodulation techniques to coherent spatial frequency domain imaging to extract optical properties and speckle flow index from a single snapshot. Applying this technique to forearm reactive hyperemia protocols demonstrates the ability to resolve intrinsic physiological signals such as the heart beat waveform and the buildup of deoxyhemoglobin associated with oxygen consumption.

Fluorescence tomography (FT) is a promising molecular imaging technique that can spatially resolve both fluorophore concentration and lifetime parameters. However, recovered fluorophore parameters highly depend on the size and depth of the object due to the ill-posedness of the FT inverse problem. Structural a priori information from another high spatial resolution imaging modality has been demonstrated to significantly improve FT reconstruction accuracy. In this study, we have constructed a combined magnetic resonance imaging (MRI) and FT system for small animal imaging. A photo-multiplier tube (PMT) is used as the detector to acquire frequency domain FT measurements. This is the first MR-compatible time-resolved FT system that can reconstruct both fluorescence concentration and lifetime maps simultaneously. The performance of the hybrid system is evaluated with phantom studies. Two different fluorophores, Indocyanine Green (ICG) and 3-3′ Diethylthiatricarbocyanine Iodide (DTTCI), which have similar excitation and emission spectra but different lifetimes, are utilized. The fluorescence concentration and lifetime maps are both reconstructed with and without the structural a priori information obtained from MRI for comparison. We show that the hybrid system can accurately recover both fluorescence intensity and lifetime within 10% error for two 4.2 mm-diameter cylindrical objects embedded in a 38 mm-diameter cylindrical phantom when MRI structural a priori information is utilized.

High scattering in biological tissues makes fluorescence tomography inverse problem very challenging in thick medium. We describe an approach termed "temperature-modulated fluorescence tomography" that can acquire fluorescence images at focused ultrasound resolution. By utilizing recently emerged temperature sensitive fluorescence contrast agents, this technique provides fluorescence images with high resolution prior to any reconstruction process. We demonstrate that this technique is well suited to resolve small fluorescence targets located several centimeters deep in tissue.

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Diffuse Optical Tomography (DOT) is an optical imaging modality that has various clinical applications. However, the spatial resolution and quantitative accuracy of DOT is poor due to strong photon scatting in biological tissue. Structural a priori information from another high spatial resolution imaging modality such as Magnetic Resonance Imaging (MRI) has been demonstrated to significantly improve DOT accuracy. In addition, a contrast agent can be used to obtain differential absorption images of the lesion by using dynamic contrast enhanced DOT (DCE-DOT). This produces a relative absorption map that consists of subtracting a reconstructed baseline image from reconstructed images in which optical contrast is included. In this study, we investigated and compared different reconstruction methods and analysis approaches for regular endogenous DOT and DCE-DOT with and without MR anatomical a priori information for arbitrarily-shaped objects. Our phantom and animal studies have shown that superior image quality and higher accuracy can be achieved using DCE-DOT together with MR structural a priori information. Hence, implementation of a combined MRI-DOT system to image ICG enhancement can potentially be a promising tool for breast cancer imaging.

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