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While survival of children with complex congenital heart defects has improved in recent years, roughly half suffer neurological deficits suspected to be related to cerebral ischemia. Here we report the first demonstration of optical diffuse correlation spectroscopy (DCS) for continuous and non-invasive monitoring of cerebral microvascular blood flow during complex human neonatal or cardiac surgery. Comparison between DCS and Doppler ultrasound flow measurements during deep hypothermia, circulatory arrest, and rewarming were in good agreement. Looking forward, DCS instrumentation, alone and with NIRS, could provide access to flow and metabolic biomarkers needed by clinicians to adjust neuroprotective therapy during surgery.

We introduce, validate and demonstrate a new software correlator for high-speed measurement of blood flow in deep tissues based on diffuse correlation spectroscopy (DCS). The software correlator scheme employs standard PC-based data acquisition boards to measure temporal intensity autocorrelation functions continuously at 50 – 100 Hz, the fastest blood flow measurements reported with DCS to date. The data streams, obtained in vivo for typical source-detector separations of 2.5 cm, easily resolve pulsatile heart-beat fluctuations in blood flow which were previously considered to be noise. We employ the device to separate tissue blood flow from tissue absorption/scattering dynamics and thereby show that the origin of the pulsatile DCS signal is primarily flow, and we monitor cerebral autoregulation dynamics in healthy volunteers more accurately than with traditional instrumentation as a result of increased data acquisition rates. Finally, we characterize measurement signal-to-noise ratio and identify count rate and averaging parameters needed for optimal performance.

We develop and validate a Modified Beer-Lambert law for blood flow based on diffuse correlation spectroscopy (DCS) measurements. The new formulation enables blood flow monitoring from temporal intensity autocorrelation function data taken at single or multiple delay-times. Consequentially, the speed of the optical blood flow measurement can be substantially increased. The scheme facilitates blood flow monitoring of highly scattering tissues in geometries wherein light propagation is diffusive or non-diffusive, and it is particularly well-suited for utilization with pressure measurement paradigms that employ differential flow signals to reduce contributions of superficial tissues.

Quantitative phase imaging (QPI) utilizes the fact that the phase of an imaging field is much more sensitive than its amplitude. As fields from the source interact with the specimen, local variations in the phase front are produced, which provide structural information about the sample and can be used to reconstruct its topography with nanometer accuracy. QPI techniques do not require staining or coating of the specimen and are therefore nondestructive. Diffraction phase microscopy (DPM) combines many of the best attributes of current QPI methods; its compact configuration uses a common-path off-axis geometry which realizes the benefits of both low noise and single-shot imaging. This unique collection of features enables the DPM system to monitor, at the nanoscale, a wide variety of phenomena in their natural environments. Over the past decade, QPI techniques have become ubiquitous in biological studies and a recent effort has been made to extend QPI to materials science applications. We briefly review several recent studies which include real-time monitoring of wet etching, photochemical etching, surface wetting and evaporation, dissolution of biodegradable electronic materials, and the expansion and deformation of thin-films. We also discuss recent advances in semiconductor wafer defect detection using QPI.

A pilot study explores relative contributions of extra-cerebral (scalp/skull) versus brain (cerebral) tissues to the blood flow index determined by diffuse correlation spectroscopy (DCS). Microvascular DCS flow measurements were made on the head during baseline and breath-holding/hyperventilation tasks, both with and without pressure. Baseline (resting) data enabled estimation of extra-cerebral flow signals and their pressure dependencies. A simple two-component model was used to derive baseline and activated cerebral blood flow (CBF) signals, and the DCS flow indices were also cross-correlated with concurrent Transcranial Doppler Ultrasound (TCD) blood velocity measurements. The study suggests new pressure-dependent experimental paradigms for elucidation of blood flow contributions from extra-cerebral and cerebral tissues.

"Diffuse correlation spectroscopy" (DCS) is a technology for non-invasive transcranial measurement of cerebral blood flow (CBF) that can be hybridized with "near-infrared spectroscopy" (NIRS). Taken together these methods hold potential for monitoring hemodynamics in stroke patients. We explore the utility of DCS and NIRS to measure effects of head-of-bed (HOB) positioning at 30 degrees , 15 degrees , 0 degrees , -5 degrees and 0 degrees angles in patients with acute ischemic stroke affecting frontal cortex and in controls. HOB positioning significantly altered CBF, oxy-hemoglobin (HbO(2)) and total-hemoglobin (THC) concentrations. Moreover, the presence of an ipsilateral infarct was a significant effect for all parameters. Results are consistent with the notion of impaired CBF autoregulation in the infarcted hemisphere.

We present three-dimensional (3D) in vivo images of human breast cancer based on fluorescence diffuse optical tomography (FDOT). To our knowledge, this work represents the first reported 3D fluorescence tomography of human breast cancer in vivo. In our protocol, the fluorophore Indocyanine Green (ICG) is injected intravenously. Fluorescence excitation and detection are accomplished in the soft-compression, parallel-plane, transmission geometry using laser sources at 786 nm and spectrally filtered CCD detection. Phantom and in vivo studies confirm the signals are due to ICG fluorescence, rather than tissue autofluorescence and excitation light leakage. Fluorescence images of breast tumors were in good agreement with those of MRI, and with DOT based on endogenous contrast. Tumorto- normal tissue contrast based on ICG fluorescence was two-to-four-fold higher than contrast based on hemoglobin and scattering parameters. In total the measurements demonstrate that FDOT of breast cancer is feasible and promising.

We combine diffuse optical and correlation spectroscopies to simultaneously measure the oxyhemoglobin and deoxyhemoglobin concentration and blood flow in an adult human brain during sensorimotor stimulation. The observations permit calculation of the relative cerebral metabolic rate of oxygen in the human brain, for the first time to our knowledge, by use of all-optical methods. The feasibility for noninvasive optical measurement of blood flow through the skull of an adult brain is thus demonstrated, and the clinical potential of this hybrid, all-optical noninvasive, methodology can now be explored.

We report in vivo imaging of neuronal electrical activity from superficial layers of the mouse barrel cortex. The measurements have approximately 16-microm spatial and 3-ms temporal resolution and reach depths of 150 microm below the cortical surface. The depth-dependent differential-fluorescence optical sections of activity are consistent with known cortical architecture and represent an important step toward in vivo measurement of functioning complex neural networks. Our observations employ a custom gradient-index lens probe and voltage-sensitive dye fluorescence; the use of epi-illumination rather than dark-field illumination provides the dramatic signal-to-noise improvement necessary for fast three-dimensional imaging.

A novel frequency-domain multiplexing system has been developed for in vivo measurements of rapid cerebral hemodynamics. The instrument operates in the frequency-domain with three optical wavelengths, six source positions, and two detectors. Frequency-division multiplexing was used to modulate three wavelengths (690, 786, and 830 nm) at slightly different frequencies around 70 MHz. The three laser output beams were combined and switched into different source positions by use of fast optical switches (switch time

This work reports an investigation of the fluorescent field re-emitted by an object embedded in a highly scattering media illuminated by two-interfering sources. Simulations in the frequency domain with a finite difference method solving the diffusion equation were performed. The media considered had features typical of a soft-compressed breast. An absorbing-fluorescent inhomogeneity was embedded in the center of the slab. A qualitative study of the re-emitted field was achieved. The re-emitted field was found to possess unique features characteristic of the two-interfering sources excitation, i.e. null intensity when the object was between the two sources and a 180 degrees transition crossing this position. Those features, when performing a scan of the two sources, permitted accurate localization of the inhomogeneity. Moreover, even when the detector was not placed on the mid-plane of the two sources, the re-emitted field still exhibited the interfering characteristic pattern, which was not seen at the excitation wavelength. Thus, for such configurations, the re-emitted field still possessed the specific sensitivity of phased array emission conversely to the excitation wavelength.

We formulate a perturbative solution for the heterogeneous diffusion equation which demonstrates how to use differential changes in diffuse light transmission to construct images of tissue absorption changes following contrast agent administration. The analysis exposes approximations leading to an intuitive and simplified inverse algorithm, shows explicitly why transmission geometries are less susceptible to error than the remission geometries, and why differential measurements are less susceptible to surface artifacts. These ideas about differential diffuse optical tomography are not only applicable to tumor detection and characterization using contrast agents, but also to functional activation studies with or without contrast agents and multiple-wavelength measurements.

We introduce an imaging technique that combines complementary features of ultrasound and near-infrared diffusive light imaging. We achieve the combined technology experimentally by mounting an ultrasound array together with multiple laser source and optical detector fibers upon a hand-held probe. The technique is demonstrated with tissue phantoms wherein both acoustic and optical sensors image the volume underneath the probe. Coregistration of acoustic and optical images is achieved with an accuracy of 0.27+/-0.20cm, approximately half of the image pixel size of our prototype. Accurate determination of target optical absorption is also achieved by use of image segmentation on the ultrasound reconstruction. The combined technique may provide improved breast-cancer detection sensitivity and specificity.

We present a detailed theoretical, experimental, and numerical study of light diffusion and diffusing-wave spectroscopy in nematic liquid crystals. We report on experiments showing that the transport of light energy is governed by an anisotropic correlation diffusion equation, and we measure the parallel and the perpendicular components of the diffusion tensor and the diffusing-wave spectroscopy temporal decay rate. We derive theoretically the correlation diffusion equations. We then calculate the diffusing-wave spectroscopy temporal decay rate, and we provide explicit approximate, yet accurate, expressions for the components of the light diffusion tensor, which we evaluate numerically as a function of material parameters of nematics. Using the actual scattering cross sections for a nematic, we simulate photon transport and verify that it is described at long times by an anisotropic diffusion equation with diffusion coefficients in excellent agreement with both those obtained experimentally and those obtained from our analytical expressions.

The diffusion of correlation is used to detect, localize, and characterize dynamical and optical spatial inhomogeneities in turbid media and is accurately modeled by a correlation diffusion equation. We demonstrate experimentally and with Monte Carlo simulations that the transport of correlation can be viewed as a correlation wave {analogous to a diffuse photon-density wave [Phys. Today48, 34 (1995)]} that propagates spherically outward from sources and scatters from macroscopic spatial variations in dynamical and/or optical properties. We demonstrate the utility of inverse scattering algorithms for reconstructing images of the spatially varying dynamical properties of turbid media. The biomedical applicability of this diffuse correlation probe is illustrated in studies of the depth of burned tissues.

We present analytic solutions for fluorescent diffuse photon density waves originating from fluorophores distributed in thick turbid media. Solutions are derived for a homogeneous turbid medium containing a uniform distribution of fluorophores and for a system that is homogeneous except for the presence of a single spherical inhomogeneity Generally the inhomogeneity has fluorophore concentration, and lifetime and optical properties that differ from those of the background. The analytic solutions are verified by numerical calculations and are used to determine the fluorophore lifetime and concentration changes required for the accurate detection of inhomogeneities in biologically relevant systems. The relative sensitivities of absorption and fluorescence methods are compared.

We present images of heterogeneous turbid media derived from measurements of diffuse photon-density waves traveling through highly scattering tissue phantoms. To our knowledge, the images are the first experimental reconstruction based on data collected in the frequency domain. We demonstrate images of both absorbing and scattering heterogeneities and show that this method is sensitive to the optical properties of the heterogeneity. The algorithm employs a differential measurement scheme that reduces the effect of errors resulting from incorrect estimation of the background optical properties. The relative advantages of sources with low and high modulation frequency are discussed within this context.

Second-harmonic generation and linear photomodulation are combined to study free-charge trapping mechanisms at ZnSe–GaAs(001) heterointerfaces. The variation of second-harmonic intensity as a function of charged-trap density at the buried junction is analyzed quantitatively and used with time-dependent measurements to determine interfacial charge-trap lifetimes.

Diffusing-wave spectroscopy (DWS) experiments require the choice of suitable sample geometry. We study sample geometries for transmission experiments by performing DWS measurements on a variable thickness cell. The data reveal that DWS works well, giving consistent answers to within 5% when the cell is more than 10 random walk step lengths thick, and that the input geometry is less significant when sample cells are immersed in water than when they are surrounded by air. Further, we see that the applicability of the diffusion approximation depends on the anisotropy of individual scattering events.

We describe and characterize an experimental apparatus that generates tunable infrared light pulses from 3.4 to 7.0 μm by difference-frequency mixing in AgGaS2. The pulses are 2.16 ps in duration, have a frequency bandwidth of 6.6 cm−1, and are produced at a 76-MHz repetition rate. Because the apparatus is compatible with low signal lock-in modulation and signal-averaging techniques, the infrared probe pulses can be used to measure very small (

We have studied the temporal profile of photon-echo signals generated by combined gated cw and pulsed dye-laser excitation of the inhomogeneously broadened, 555.6-nm absorption line of (174)Yb vapor. We find that the echo profile is, after time reversal, essentially identical with that of the first excitation pulse. We give a new analysis of this effect. Since time-reversed pulse reproduction should also occur in inhomogeneously broadened solid samples, and since we observe time-reversed reproduced pulses up to 4% as intense as the input pulse, this effect may have important applications in optical signal-processing systems.