This PDF file contains the front matter associated with SPIE Proceedings Volume 9538, including the Title Page, Copyright information, Table of Contents, Authors, Introduction (if any), and Conference Committee listing.

We developed a novel scanning system that relies on gated detection of late photons at short source-detector separation, enabling the recording of absorption changes in deep tissue compartments. The tissue was scanned by a galvanometer scanner from a distance of more than 10 cm, with a fixed separation of the illumination and the detection spot of a few mm. The light source was a supercontinuum laser with an acousto-optic tunable filter that was used to rapidly switch between two wavelength bands centered at 760 nm and 860 nm. A fast-gated single-photon avalanche diode was employed to eliminate the intense early part of the diffusely remitted signal and to detect photons with long times of flight with improved signal-to-noise ratio. A second detection channel contained a non-gated detector. The gated and non-gated time-of-flight distributions of photons were recorded by imaging time-correlated single photon counting synchronized with the movement of the scanner. A tissue area with dimensions of several cm was scanned with 32×32 pixels within a frame time of 1 s. Sensitivity and spatial resolution of the system were characterized by phantom measurements. In-vivo tests included functional brain activation by various tasks and demonstrated the feasibility of non-contact imaging of hemodynamic changes in the cerebral cortex.

Previous studies have showed only regions with a sensitivity higher that 1% of the maximum value can affect the recovery result for diffuse optical tomography (DOT). Two methods of efficient sensitivity map generation based on Finite Element Models (FEM) are developed based on (1) reduced sensitivity matrix and (2) parallelisation process. Time and memory efficiency of these processes are evaluated and compared with conventional methods. It is shown that the computational time for a full head model containing 200k nodes is reduced from 3 hours to 48 minutes and the required memory is reduced from 5.5 GB to 0.5 GB. For a range of mesh densities up to 320k nodes, the required memory is improved by ~1000% and computational time by ~400% to allow near real-time image recovery.

We conducted a preclinical assessment on young macaques aimed at detecting white matter lesions. We present the protocol we implemented to achieve the lesions detection using a bedside non-invasive optical-based Time-Resolved instrumentation we have optimized for this purpose. We validated the reconstructed 3D absorption map with co-registration of MRI data.

Diffuse optics is a powerful tool for clinical applications ranging from oncology to neurology, but also for molecular imaging, and quality assessment of food, wood and pharmaceuticals. We show that ideally time-domain diffuse optics can give higher contrast and a higher penetration depth with respect to standard technology. In order to completely exploit the advantages of a time-domain system a distribution of sources and detectors with fast gating capabilities covering all the sample surface is needed. Here, we present the building block to build up such system. This basic component is made of a miniaturised source-detector pair embedded into the probe based on pulsed Vertical-Cavity Surface-Emitting Lasers (VCSEL) as sources and Single-Photon Avalanche Diodes (SPAD) or Silicon Photomultipliers (SiPM) as detectors. The possibility to miniaturized and dramatically increase the number of source detectors pairs open the way to an advancement of diffuse optics in terms of improvement of performances and exploration of new applications. Furthermore, availability of compact devices with reduction in size and cost can boost the application of this technique.

Near-infrared diffuse optical tomography (DOT) is a medical imaging which gives the distribution of the optical properties of biological tissues. To obtain endogenous chromophore features in the depth of a scattering medium, a multiwavelength/time-resolved (MW/TR) DOT setup was used. Reconstructions of the three-dimensional maps of chromophore concentrations of probed media were obtained by using a data processing technique which manages Mellin-Laplace Transforms of their MW/TR optical signals and those of a known reference medium. The point was to put a constraint on the medium absorption coefficient by using a material basis composed of a given set of chromophores of known absorption spectra. Experimental measurements were conducted by injecting the light of a picosecond near- infrared laser in the medium of interest and by collecting, for several wavelengths and multiple positions, the backscattered light via two fibers (with a source-detector separation of 15 mm) connected to fast-gated single-photon avalanche diodes (SPAD) and coupled to a time-correlated single-photon counting (TCSPC) system. Validations of the method were performed in simulation in the same configuration as the experiments for different combination of chromophores. Evaluation of the technique in real conditions was investigated on liquid phantoms composed of an homogenous background and a 10 mm depth inclusion formed of combination of intralipid and inks scanned at 30 positions and at three wavelengths. Both numerical and preliminary phantom experiments confirm the potential of this method to determine chromophore concentrations in the depth of biological tissues.

Exact and efficient analytical solutions of the three dimensional radiative transport equation in the spatial frequency, the spatial, the temporal frequency, and time domains were derived for two-layered scattering media. Index mismatched boundary conditions based on Fresnel's equations were implemented and arbitrary rotational symmetric phase functions were applied to characterize the scattering in the turbid media. Solutions were derived for obliquely incident beams having arbitrary spatial profiles. The derived analytical solutions were successfully validated with Monte Carlo simulations and partly compared with analytical solutions of the diffusion equation for two-layered scattering media.

We present a technique for determining the scattering coefficient of epithelial tissue from diffuse reflectance measurements due to an obliquely incident Gaussian beam. This method applies the convolution form of the diffuse reflectance as determined by the corrected diffusion approximation.

One of the major challenges within Optical Imaging, photon propagation through clear layers embedded between scattering tissues, can be now efficiently modelled in real-time thanks to the Monte Carlo approach based on GPU. Because of its nature, the photon propagation problem can be very easily parallelized and ran on low cost hardware, avoiding the need for expensive Super Computers. A comparison between Diffusion and MC photon propagation theory is presented in this work with application to neuroimaging, investigating low scattering regions in a mouse-like phantom. Regions such as the Cerebral Spinal Fluid, are currently not taken into account in the classical computational models because of the impossibility to accurately simulate light propagation using fast Diffusive Equation approaches, leading to inaccuracies during the reconstruction process. The goal of the study presented here, is to reduce and further improve the computation accuracy of the reconstructed solution in a highly realistic scenario in the case of neuroimaging in preclinical mouse models.

We present for the first time the analytical solution for the simplified spherical harmonics equations with partial reflective boundary conditions for a point source inside a spherical homogenous turbid medium.

An important issue in tissue optics and Optical Tomography is to have an efficient forward solver. In this work, a new numerical algorithm was developed for solving light propagation with the radiative transport equation within a three-dimensional absorbing and a highly forward-scattering medium such as a biological tissue subjected to an incident beam. Both elastically scattered light and fluorescence light were studied. Two steady state problems used to assess the performance and accuracy of the proposed algorithm are presented. We show that it is possible to obtain a good level of accuracy with a deterministic numerical method: relative differences less than 1.7% and 4.5% were obtained when compared against Monte Carlo solutions for problems of elastically scattered light and fluorescence light, respectively.

Bioluminescence imaging (BLI) is a widely used pre-clinical imaging technique, but there are a number of limitations to its quantitative accuracy. This work uses an animal model to demonstrate some significant limitations of BLI and presents processing methods and algorithms which overcome these limitations, increasing the quantitative accuracy of the technique. The position of the imaging subject and source depth are both shown to affect the measured luminescence intensity. Free Space Modelling is used to eliminate the systematic error due to the camera/subject geometry, removing the dependence of luminescence intensity on animal position. Bioluminescence tomography (BLT) is then used to provide additional information about the depth and intensity of the source. A substantial limitation in the number of sources identified using BLI is also presented. It is shown that when a given source is at a significant depth, it can appear as multiple sources when imaged using BLI, while the use of BLT recovers the true number of sources present.

We have developed a hybrid approach to investigate the dynamics of perfusion and oxygenation in the kidney of rats under pathophysiologically relevant conditions. Our approach combines near-infrared spectroscopy to quantify hemoglobin concentration and oxygen saturation in the renal cortex, and an invasive probe method for measuring total renal blood flow by an ultrasonic probe, perfusion by laser-Doppler fluxmetry, and tissue oxygen tension via fluorescence quenching. Hemoglobin concentration and oxygen saturation were determined from experimental data by a Monte Carlo model. The hybrid approach was applied to investigate and compare temporal changes during several types of interventions such as arterial and venous occlusions, as well as hyperoxia, hypoxia and hypercapnia induced by different mixtures of the inspired gas. The approach was also applied to study the effects of the x-ray contrast medium iodixanol on the kidney.

We present a new setup for time-resolved diffuse optical tomography based on multiple source-detector acquisitions analysed by means of the Mellin-Laplace transform. The proposed setup has been used to perform pre-clinical measurements on rats in order to show its suitability for non-invasive assessment of flap viability.

We propose a simple and reliable solid phantom for mimicking realistic localized absorption changes within a diffusive medium. The phantom is based on a solid matrix holding a movable black inclusion embedded in a rod. Translating the rod parallel to the phantom surface, the inhomogeneity can be positioned beneath the source-detector pair (perturbed case) or far from it (unperturbed case). Examples of time-resolved transmittance measurements and time-resolved reflectance scans are shown to demonstrate the properties and the versatility of the phantom.

We report on the design, performance assessment, and first in vivo measurement of a Time-Resolved Diffuse Optical system for broadband (600-1350 nm) nm measurement of absorption and scattering spectra of biological tissues for non-invasive clinical diagnostics. Two strategies to reduce drift and enhance responsivity are adopted. The system was enrolled in a first in vivo test phase on healthy volunteers, carrying out non-invasive, in vivo quantification of key tissue constituents (oxy- and deoxy-hemoglobin, water, lipids, collagen) and tissue micro-structure (scatterer size and density).

We present an experimental characterization of an optical phantom system based on epoxy resin using two different kinds of scatterers: TiO₂ and Al₂O₃. A combination of both scattering materials allows adjusting the anisotropy value of the phase function g or the phase function related parameter γ . As part of this work, both scattering agents are extensively studied.

We validate a non-contact Diffuse Reflectance Spectroscopy (DRS) system as a first stage to approach quantitative multi-spectral imaging technique. The non-contact DRS system with separated illumination and detection paths was developed with different progressive set-ups which were all compared to a well-founded contact DRS system. While quantitation of the absorption coefficient is well achieved with the existing method, the calculation of the scattering coefficient is deteriorated by the non-contact architecture measurements. We have therefore developed an adaptive reference-based algorithm to compensate for this effect.

We report a broadband time-resolved characterization of selected bony prominence locations of the human body. A clinical study was performed at six different bony prominence locations of 53 subjects. A portable broadband time-resolved system equipped with pulse drift and distortion compensation strategy was used for absorption and scattering measurements. Key tissue constituents were quantified as a pilot step towards non-invasive optical assessment of bone pathologies.

In reflectance spectroscopy, a major concern is the possibility to discriminate signals coming from different layers of the investigated medium. In this work, the case of time-domain near infrared spectroscopy of muscle is studied with particular attention in the estimation of the pathlength in the different tissue’s layers and its impact in the calculation of chromophores concentration.

Peripheral Arterial Disease (PAD) is caused by a reduction of the internal diameters of the arteries in the upper or lower extremities mainly due to atherosclerosis. If not treated, its worsening may led to a complete occlusion, causing the death of the cells lacking proper blood supply, followed by gangrene that may require chirurgical amputation. We have recently performed a clinical study in which good sensitivities and specificities were achieved with dynamic diffuse optical tomography. To gain a better understanding of the physiological foundations of many of the observed effects, we started to develop a mathematical model for PAD. The model presented in this work is based on a multi-compartment Windkessel model, where the vasculature in the leg and foot is represented by resistors and capacitors, the blood pressure with a voltage drop, and the blood flow with a current. Unlike existing models, the dynamics induced by a thigh-pressure-cuff inflation and deflation during the measurements are taken into consideration. This is achieved by dynamically varying the resistances of the large veins and arteries. By including the effects of the thigh-pressure cuff, we were able to explain many of the effects observed during our dynamic DOT measurements, including the hemodynamics of oxy- and deoxy-hemoglobin concentration changes. The model was implemented in MATLAB and the simulations were normalized and compared with the blood perfusion obtained from healthy, PAD and diabetic patients. Our preliminary results show that in unhealthy patients the total system resistance is sensibly higher than in healthy patients.

We explored evidence that a combination of dynamic and static diffuse optical tomography can be used to predict treatment response in patients undergoing neo adjuvant chemotherapy. Both blood chromophore concentrations and hemodynamic signatures were measured over the 5-month course of treatment.

Time domain multi-wavelength (635 to 1060 nm) optical mammography was performed on 200 subjects to estimate their average breast tissue composition in terms of oxy- and deoxy-hemoglobin, water, lipid and collagen, and structural information, as provided by scattering parameters (amplitude and power). Significant (and often marked) dependence of tissue composition and structure on age, menopausal status, body mass index, and use of oral contraceptives was demonstrated.

A retrospective pilot clinical study on time domain multi-wavelength (635 to 1060 nm) optical mammography was exploited to assess collagen as a breast-cancer risk factor on a total of 109 subjects (53 healthy and 56 with malignant lesions). An increased cancer occurrence is observed on the 15% subset of patients with higher age-matched collagen content. Further, a similar clustering based on the percentage breast density leads to a different set of patients, possibly indicating collagen as a new independent breast cancer risk factor. If confirmed statistically and on larger numbers, these results could have huge impact on personalized diagnostics, health care systems, as well as on basic research.

Time domain multi-wavelength (635 to 1060 nm) optical mammography was performed on 82 subjects with breast lesions (45 malignant and 38 benign lesions). A perturbative approach based on the high-order calculation of the pathlength of photons inside the lesion was applied to estimate differences between lesion and average healthy tissue of the same breast in terms of: i) absorption properties, and ii) concentration of the major tissue constituents (oxy- and deoxy-hemoglobin, water, lipid and collagen). The absorption difference Δμ_a between lesion and healthy tissue is significantly different for malignant vs. benign lesions at all wavelengths. Logistic regression fitted to the absorption data identifies 975 nm as the key wavelength to discriminate malignant from benign lesions. When the difference in tissue composition between lesion and healthy tissue is considered, malignant lesions are characterized by significantly higher collagen content than benign lesions. Also the best model for the discrimination of malignant lesions obtained applying regression logistic to tissue composition is based only on collagen. Including demographic information into the model improves its specificity.

Near infrared spectroscopy (NIRS) has potential to offer a fast and non-invasive method of assessing cerebral saturation in a clinical setting, however, there are concerns that NIRS brain measures suffer contamination from superficial tissues. This study used the Valsalva manoeuver (VM) to determine whether NIRS could differentiate between superficial (from somatic tissue) and neurological changes in the context of traumatic brain injury. A potent vasopressor was used to assess the effect of reducing total haemoglobin concentration in the superficial regions of the forehead. Frequency domain NIRS measurements during the VM pre and post vasoconstrictor injection, combined with simulation data, conclusively show that NIRS can detect neurological changes, in both haemoglobin content and saturation, when positioned on the forehead. The effect of superficial contamination in this instance appeared to be insignificant, with no statistically significant change in saturation over 8 patients, even with a drop in superficial haemoglobin concentration due to the vasoconstrictor, confirmed by laser Doppler. Nevertheless, simulations indicated that the absolute values of the recovered NIRS parameters are not quantitatively accurate; however a direct comparison with invasive measures is needed to confirm this.

We present a method for acquiring whole-head images of changes in blood volume and oxygenation from the infant brain at cot-side using time-resolved diffuse optical tomography (TR-DOT). At UCL, we have built a portable TR-DOT device, known as MONSTIR II, which is capable of obtaining a whole-head (1024 channels) image sequence in 75 seconds. Datatypes extracted from the temporal point spread functions acquired by the system allow us to determine changes in absorption and reduced scattering coefficients within the interrogated tissue. This information can then be used to define clinically relevant measures, such as oxygen saturation, as well as to reconstruct images of relative changes in tissue chromophore concentration, notably those of oxy- and deoxyhaemoglobin. Additionally, the effective temporal resolution of our system is improved with spatio-temporal regularisation implemented through a Kalman filtering approach, allowing us to image transient haemodynamic changes. By using this filtering technique with intensity and mean time-of-flight datatypes, we have reconstructed images of changes in absorption and reduced scattering coefficients in a dynamic 2D phantom. These results demonstrate that MONSTIR II is capable of resolving slow changes in tissue optical properties within volumes that are comparable to the preterm head. Following this verification study, we are progressing to imaging a 3D dynamic phantom as well as the neonatal brain at cot-side. Our current study involves scanning healthy babies to demonstrate the quality of recordings we are able to achieve in this challenging patient population, with the eventual goal of imaging functional activation and seizures.

In this study the formation of a surface layer on top of an Intralipid dilution was studied. By use of spatial frequency reflectance and spatially resolved reflectance the surface layer could be characterized. The influence on the determination of the optical properties assuming a semi-infinite medium in the theory was investigated. By use of an angularly resolved reflectance device the formation even on a horizontally orientated glass slide could be shown.

Optical imaging through complex biological media remains a very challenging task due to the extremely high scattering experienced. A new design scanner is proposed and modelled which images scatter spatio-temporally. Modeling confirms the performance of the design. The inversion algorithm to reconstruct the scattering object remains as future work.

The subject of superficial contamination and signal origins remains a widely debated topic in the field of Near Infrared Spectroscopy (NIRS), yet the concept of using the technology to monitor an injured brain, in a clinical setting, poses additional challenges concerning the quantitative accuracy of recovered parameters.

Using high density diffuse optical tomography probes, quantitatively accurate parameters from different layers (skin, bone and brain) can be recovered from subject specific reconstruction models. This study assesses the use of registered atlas models for situations where subject specific models are not available. Data simulated from subject specific models were reconstructed using the 8 registered atlas models implementing a regional (layered) parameter recovery in NIRFAST. A 3-region recovery based on the atlas model yielded recovered brain saturation values which were accurate to within 4.6% (percentage error) of the simulated values, validating the technique. The recovered saturations in the superficial regions were not quantitatively accurate. These findings highlight differences in superficial (skin and bone) layer thickness between the subject and atlas models. This layer thickness mismatch was propagated through the reconstruction process decreasing the parameter accuracy.

In the present contribution we investigate images of CW diffusely remitted light registered by a CCD camera imaging a turbid medium containing an absorbent and fluorescent lesion, during illumination by a point-like source. We show that a normalization technique using local background signals reconstructed from experimental data is useful to increase the contrast of both the absorption and the fluorescence channel. Using this technique, results on phantoms are given which demonstrate that lesions with clinically-realistic fluorophore and absorber concentrations can be detected. Results are compared with theoretical calculations as well.

Diffuse optical imaging of the human brain requires methods to account for the layered structure of the head. In this work we present results of experiments performed on layered phantoms in reflection geometry by a time-resolved technique. We investigate structures with two and three layers with the goal to retrieve the optical properties of the deepest one. Data analysis is based on an existing solution of the time-resolved diffusion equation for a multilayer cylinder. Using a sufficiently large source-detector separation the absorption and reduced scattering coefficients of the deepest layer can be derived from time-resolved reflectance with a deviation of typically not more than 10% from the known values.

We discuss the determination of optical properties of thick scattering media from measurements of time-resolved transmittance by diffusion theory using Monte Carlo simulations as a gold standard to model photon migration. Our theoretical and experimental investigations reveal differences between calculated distributions of times of flight (DTOFs) of photons from both models which result in an overestimation of the absorption and the reduced scattering coefficient by diffusion theory which becomes larger for small scattering coefficients. By introducing a temporal shift in the DTOFs obtained with the diffusion model as additional fit parameter, the deviation in the absorption coefficient can be compensated almost completely. If the scattering medium is additionally covered by transparent layers (e.g. glass plates) the deviation between the DTOFs from both models is even larger which mainly effects the determination of the reduced scattering coefficient by diffusion theory. A temporal shift improves the accuracy of the optical properties derived by diffusion theory in this case as well.

The non-invasive research of information inside biological tissues can be made by means of setups using continuous, time-dependent or frequency modulated light sources, which emit in the visible or near-infrared range. Moreover, the biological structures such as brain, breast or fruits, can be regarded as closer to a spherical shape than a slab. This paper focus on the retrieval of tissue optical parameters in a spherical geometry using fittings with analytical solutions adapted for semi-infinite geometry. The data were generated using three different optical spectroscopy methods: frequency-resolved, spatially-resolved, and time-resolved modes. Simulations based on a Monte Carlo code were performed on homogeneous spheres, with 18 spaced detectors located on their boundary. First, data are examined in the frequency domain. Second, they are treated with optimization algorithms to assess the optical coefficients. The computations show that the spatially-resolved measurements are often more robust than those related to the frequency-resolved mode. In the temporal domain, errors on the estimates are also exhibited with the fitting by the Fourier transform of a solution based on the semi-infinite geometry. Furthermore, when the analytical solution is modified by taking into account the spherical shape, the retrieval of the coefficients is improved.

Improved cerebral monitoring systems are needed to prevent preterm infants from long-term cognitive and motor restrictions. Combining advanced near-infrared diffuse spectroscopy measurement technologies, time-resolved spectroscopy (TRS) and diffuse correlation spectroscopy (DCS) will introduce novel indicators of cerebral oxygen metabolism and blood flow for neonatology. For non-invasive sensing a fiber-optical probe is used to send and receive light from the infant head. In this study we introduce a new fiber-based hybrid probe that is designed for volume production. The probe supports TRS and DCS measurements in a cross geometry, thus both technologies gain information on the same region inside the tissue. The probe is highly miniaturized to perform cerebral measurements on heads of extreme preterm infants down to head diameters of 6cm. Considerations concerning probe production focus on a reproducible accuracy in shape and precise optical alignment. In this way deviations in measurement data within a series of probes should be minimized. In addition to that, requirements for clinical use like robustness and hygiene are considered. An additional soft-touching sleeve made of FDA compatible silicone allows for a flexible attachment with respect to the individual anatomy of each patient. We present the technical concept of the hybrid probe and corresponding manufacturing methods. A prototype of the probe is shown and tested on tissue phantoms as well as in vivo to verify its operational reliability.