Enhanced diffuse optical tomographic reconstruction using concurrent ultrasound information.

Multimodal imaging is an active branch of research as it has the potential to improve common medical imaging techniques. Diffuse optical tomography (DOT) is an example of a low resolution, functional imaging modality that typically has very low resolution due to the ill-posedness of its underlying inverse problem. Combining the functional information of DOT with a high resolution structural imaging modality has been studied widely. In particular, the combination of DOT with ultrasound (US) could serve as a useful tool for clinicians for the formulation of accurate diagnosis of breast lesions. In this paper, we propose a novel method for US-guided DOT reconstruction using a portable time-domain measurement system. B-mode US imaging is used to retrieve morphological information on the probed tissues by means of a semi-automatical segmentation procedure based on active contour fitting. A two-dimensional to three-dimensional extrapolation procedure, based on the concept of distance transform, is then applied to generate a three-dimensional edge-weighting prior for the regularization of DOT. The reconstruction procedure has been tested on experimental data obtained on specifically designed dual-modality silicon phantoms. Results show a substantial quantification improvement upon the application of the implemented technique. This article is part of the theme issue 'Synergistic tomographic image reconstruction: part 2'.

Time-domain diffuse optics with 8.6 mm2 fast-gated SiPM for extreme light harvesting.

Fast time-gated single-photon detectors demonstrated high depth sensitivity in the detection of localized absorption perturbations inside scattering media, but their use for in vivo clinical applications-such as functional imaging of brain activation-was impaired by their small (<0.04mm2) active area. Here, we demonstrate, both on phantoms and in vivo, the performance of a fast-gated digital silicon photomultiplier (SiPM) that features an overall active area of 8.6mm2, overcoming the photon collection capability of established time-gated single-pixel detectors by orders of magnitude, enabling deep investigations within scattering media and high signal-to-noise ratios at late photon arrival times.

Probe-hosted large area silicon photomultiplier and high-throughput timing electronics for enhanced performance time-domain functional near-infrared spectroscopy.

Two main bottlenecks prevent time-domain diffuse optics instruments to reach their maximum performances, namely the limited light harvesting capability of the detection chain and the bounded data throughput of the timing electronics. In this work, for the first time to our knowledge, we overcome both those limitations using a probe-hosted large area silicon photomultiplier detector coupled to high-throughput timing electronics. The system performances were assessed based on international protocols for diffuse optical imagers showing better figures with respect to a state-of-the-art device. As a first step towards applications, proof-of-principle in-vivo brain activation measurements demonstrated superior signal-to-noise ratio as compared to current technologies.

In vivo time-domain diffuse correlation spectroscopy above the water absorption peak.

Time-domain diffuse correlation spectroscopy (TD-DCS) is a newly emerging optical technique that exploits pulsed, yet coherent light to non-invasively resolve the blood flow in depth. In this work, we have explored TD-DCS at longer wavelengths compared to those previously used in literature (i.e., 750-850 nm). The measurements were performed using a custom-made titanium-sapphire mode-locked laser, operating at 1000 nm, and an InGaAs photomultiplier as a detector. Tissue-mimicking phantoms and in vivo measurements during arterial arm cuff occlusion in n=4 adult volunteers were performed to demonstrate the proof of concept. We obtained a good signal-to-noise ratio, following the hemodynamics continuously with a relatively fast (1 Hz) sampling rate. In all the experiments, the auto-correlation functions show a decay rate approximately five-fold slower compared to shorter wavelengths. This work demonstrates the feasibility of in vivo TD-DCS in this spectral region and its potentiality for biomedical applications.

In vivo time-gated diffuse correlation spectroscopy at quasi-null source-detector separation.

We demonstrate time domain diffuse correlation spectroscopy at quasi-null source-detector separation by using a fast time-gated single-photon avalanche diode without the need of time-tagging electronics. This approach allows for increased photon collection, simplified real-time instrumentation, and reduced probe dimensions. Depth discriminating, quasi-null distance measurement of blood flow in a human subject is presented. We envision the miniaturization and integration of matrices of optical sensors of increased spatial resolution and the enhancement of the contrast of local blood flow changes.

Time domain diffuse Raman spectrometer based on a TCSPC camera for the depth analysis of diffusive media.

We present a time domain diffuse Raman spectrometer for depth probing of highly scattering media. The system is based on, to the best of our knowledge, a novel time-correlated single-photon counting (TCSPC) camera that simultaneously acquires both spectral and temporal information of Raman photons. A dedicated non-contact probe was built, and time domain Raman measurements were performed on a tissue mimicking bilayer phantom. The fluorescence contamination of the Raman signal was eliminated by early time gating (0-212 ps) the Raman photons. Depth sensitivity is achieved by time gating Raman photons at different delays with a gate width of 106 ps. Importantly, the time domain can provide time-dependent depth sensitivity leading to a high contrast between two layers of Raman signal. As a result, an enhancement factor of 2170 was found for our bilayer phantom which is much higher than the values obtained by spatial offset Raman spectroscopy (SORS), frequency offset Raman spectroscopy (FORS), or hybrid FORS-SORS on a similar phantom.

Time domain diffuse correlation spectroscopy with a high coherence pulsed source: in vivo and phantom results.

Diffuse correlation spectroscopy (DCS), combined with time-resolved reflectance spectroscopy (TRS) or frequency domain spectroscopy, aims at path length (i.e. depth) resolved, non-invasive and simultaneous assessment of tissue composition and blood flow. However, while TRS provides a path length resolved data, the standard DCS does not. Recently, a time domain DCS experiment showed path length resolved measurements for improved quantification with respect to classical DCS, but was limited to phantoms and small animal studies. Here, we demonstrate time domain DCS for in vivo studies on the adult forehead and the arm. We achieve path length resolved DCS by means of an actively mode-locked Ti:Sapphire laser that allows high coherence pulses, thus enabling adequate signal-to-noise ratio in relatively fast (~1 s) temporal resolution. This work paves the way to the translation of this approach to practical in vivo use.

Time-resolved single-photon detection module based on silicon photomultiplier: A novel building block for time-correlated measurement systems.

We present the design and preliminary characterization of the first detection module based on Silicon Photomultiplier (SiPM) tailored for single-photon timing applications. The aim of this work is to demonstrate, thanks to the design of a suitable module, the possibility to easily exploit SiPM in many applications as an interesting detector featuring large active area, similarly to photomultipliers tubes, but keeping the advantages of solid state detectors (high quantum efficiency, low cost, compactness, robustness, low bias voltage, and insensitiveness to magnetic field). The module integrates a cooled SiPM with a total photosensitive area of 1 mm(2) together with the suitable avalanche signal read-out circuit, the signal conditioning, the biasing electronics, and a Peltier cooler driver for thermal stabilization. It is able to extract the single-photon timing information with resolution better than 100 ps full-width at half maximum. We verified the effective stabilization in response to external thermal perturbations, thus proving the complete insensitivity of the module to environment temperature variations, which represents a fundamental parameter to profitably use the instrument for real-field applications. We also characterized the single-photon timing resolution, the background noise due to both primary dark count generation and afterpulsing, the single-photon detection efficiency, and the instrument response function shape. The proposed module can become a reliable and cost-effective building block for time-correlated single-photon counting instruments in applications requiring high collection capability of isotropic light and detection efficiency (e.g., fluorescence decay measurements or time-domain diffuse optics systems).

Determination of reference values for optical properties of liquid phantoms based on Intralipid and India ink.

A multi-center study has been set up to accurately characterize the optical properties of diffusive liquid phantoms based on Intralipid and India ink at near-infrared (NIR) wavelengths. Nine research laboratories from six countries adopting different measurement techniques, instrumental set-ups, and data analysis methods determined at their best the optical properties and relative uncertainties of diffusive dilutions prepared with common samples of the two compounds. By exploiting a suitable statistical model, comprehensive reference values at three NIR wavelengths for the intrinsic absorption coefficient of India ink and the intrinsic reduced scattering coefficient of Intralipid-20% were determined with an uncertainty of about 2% or better, depending on the wavelength considered, and 1%, respectively. Even if in this study we focused on particular batches of India ink and Intralipid, the reference values determined here represent a solid and useful starting point for preparing diffusive liquid phantoms with accurately defined optical properties. Furthermore, due to the ready availability, low cost, long-term stability and batch-to-batch reproducibility of these compounds, they provide a unique fundamental tool for the calibration and performance assessment of diffuse optical spectroscopy instrumentation intended to be used in laboratory or clinical environment. Finally, the collaborative work presented here demonstrates that the accuracy level attained in this work for optical properties of diffusive phantoms is reliable.

Non-contact in vivo diffuse optical imaging using a time-gated scanning system.

We report on the design and first in vivo tests of a novel non-contact scanning imaging system for time-domain near-infrared spectroscopy. Our system is based on a null source-detector separation approach and utilizes polarization-selective detection and a fast-gated single-photon avalanche diode to record late photons only. The in-vivo tests included the recording of hemodynamics during arm occlusion and two brain activation tasks. Localized and non-localized changes in oxy- and deoxyhemoglobin concentration were detected for motor and cognitive tasks, respectively. The tests demonstrate the feasibility of non-contact imaging of absorption changes in deeper tissues.

Note: Comparison between a prism-based and an acousto-optic tunable filter-based spectrometer for diffusive media.

This paper compares two continuously tunable systems for time-resolved spectroscopy of diffusive media based on a supercontinuum laser source. Two approaches for spectral selection are considered relying either on a dispersive prism or on a commercial acoustic-optic tunable filter (AOTF) device. The comparison was performed first in terms of extracted power and spectral response function, then in terms of distortions introduced in the retrieved absorption and scattering spectra. Simulations and experiments on diffusive phantoms confirmed that, besides narrower FWHM in the AOTF bandpass, the prism solution is superior with respect to the distortions produced on the recovered spectra.

Non-contact time-resolved diffuse reflectance imaging at null source-detector separation.

We report results of the proof-of-principle tests of a novel non-contact tissue imaging system. The system utilizes a quasi-null source-detector separation approach for time-domain near-infrared spectroscopy, taking advantage of an innovative state-of-the-art fast-gated single photon counting detector. Measurements on phantoms demonstrate the feasibility of the non-contact approach for the detection of optically absorbing perturbations buried up to a few centimeters beneath the surface of a tissue-like turbid medium. The measured depth sensitivity and spatial resolution of the new system are close to the values predicted by Monte Carlo simulations for the inhomogeneous medium and an ideal fast-gated detector, thus proving the feasibility of the non-contact approach for high density diffuse reflectance measurements on tissue. Potential applications of the system are also discussed.

The impact of morphology on light transport in cancellous bone.

In recent years, optical techniques based on diffusion approximation have demonstrated their ability to gain rich spectral information about bone. However, these methods normally assume homogeneity, while cancellous bone and marrow form a highly heterogeneous two-phase medium. This paper studies the limitations of this assumption, and quantifies the role of microstructure on long-range transport properties. The propagation of light pulses through trabecular bone is calculated by Monte Carlo simulation of the scattering and absorption in reconstructions of bone samples obtained from x-ray micro tomographic scans. The time-resolved responses are then fitted with the analytical response of a homogeneous material to obtain the apparent transport properties. These properties are used to test different homogenization equations that have been postulated in the past for heterogeneous tissues and to check their accuracy. The results show that nonlinearity and crosstalk between absorption and scattering are statistically significant, although their impact is relatively small. More importantly, we found that the weight of the components is not only affected by their volume fractions, but need to be corrected by other morphologic measures like trabecular spacing or connectivity density. These deviations from the homogeneous assumption are stronger for scattering than for absorption. In conclusion, the average optical properties of cancellous bone are strongly determined by its microstructure, meaning that optical techniques are a valid method for tissue evaluation, but careful consideration of structure-related perturbation sources is required.

Bandpass effects in time-resolved diffuse spectroscopy.

This paper discusses the spectral distortions occurring when time-resolved spectroscopy of diffusive media is performed illuminating with a wide bandpass. It is shown that the spectral region within the bandpass that exhibits the lowest absorption will dominate the resulting time-resolved curve, leading to significant underestimations of absorption as well as distortions in the spectral shape (including shifts in peak positions). Due to the nonlinear behavior of absorption, this effect becomes even more pronounced when including longer and longer photon path lengths. First, a theoretical treatment of the problem is given, and then the distortion is described by time-resolved reflectance simulations and experimental measurements of lipid and water samples. A spectrally constrained data analysis is proposed that takes into account the spectrum of the light injected into the sample, used to overcome the distortion and improve the accuracy of the estimation of chromophore concentrations from absorption spectra. Measurements on a lipid sample show a reduction of the error from 30% to 6%.

Time-resolved optical spectroscopy of wood.

We have proposed and experimentally demonstrated that picosecond time-resolved optical spectroscopy in the visible/near-infrared (NIR) region (700-1040 nm) is a useful technique for noninvasive characterization of wood. This technique has been demonstrated on both softwood and hardwood samples treated in different ways simulating the aging process suffered by waterlogged woods. In all the cases, alterations of absorption and scattering spectra were observed, revealing changes of chemical and structural composition.

Determination of visible near-IR absorption coefficients of mammalian fat using time- and spatially resolved diffuse reflectance and transmission spectroscopy.

In-vivo optical spectroscopy and the determination of tissue absorption and scattering properties have a central role in the development of novel optical diagnostic and therapeutic modalities in medicine. A number of techniques are available for the optical characterization of tissue in the visible near-IR region of the spectrum. An important consideration for many of these techniques is the reliability of the absorption spectrum of the various constituents of tissue. The availability of accurate absorption spectra in the range 600 to 1100 nm may allow for the determination of the concentration of key tissue constituents such as oxy- and deoxy-hemoglobin, water, and lipids. The objective of the current study is the determination of a reliable absorption spectrum of lipid(s) that can be used for component analysis of in-vivo spectra. We report the absorption spectrum of a clear purified oil obtained from pig lard. In the liquid phase above 36 degrees C, the oil is transparent and thus suitable for collimated transmission measurements. At room temperature, the oil is a solid grease that is highly scattering. The absorption and scattering properties in this solid phase are measured using time- and spatially resolved diffuse reflectance spectroscopy. Using these three independent measurement techniques, we have determined an accurate estimate for the absorption spectrum of mammalian fat.

Multi-wavelength time domain optical mammography.

A time-resolved optical mammograph operating at 7 wavelengths (637, 683, 785, 832, 905, 916, and 975 nm) in compressed breast geometry was developed. Its clinical application was started on patients bearing malignant and benign lesions. Late gated intensity images are used to obtain information on the spatial distribution of the absorption properties of breast. Scattering images derived from the diffusion theory are also applied for lesion detection and characterization. Cancers are identified in intensity images at short wavelengths, due to the high blood content, while cysts are typically characterized by low scattering at all wavelengths. The increase (from 4 to 7) in the number of wavelengths as compared to the previous versions of the instrument aims at improving the robustness of the fitting procedures for a better estimate of tissue composition and structure and of physiological parameters. Moreover, the new wavelengths contribute to the qualitatively identify tissue composition from intensity images, and could assist lesion detection.

Do shorter wavelengths improve contrast in optical mammography?

The detection of tumours with time-resolved transmittance imaging relies essentially on blood absorption. Previous theoretical and phantom studies have shown that both contrast and spatial resolution of optical images are affected by the optical properties of the background medium, and high absorption and scattering are generally beneficial. Based on these observations, wavelengths shorter than presently used (680-780 nm) could be profitable for optical mammography. A study was thus performed analysing time-resolved transmittance images at 637, 656, 683 and 785 nm obtained from 26 patients bearing 16 tumours and 15 cysts. The optical contrast proved to increase upon decreasing wavelengths for the detection of cancers in late-gated intensity images, with higher gain in contrast for lesions of smaller size (<1.5 cm diameter). For cysts either a progressive increase or decrease in contrast with wavelength was observed in scattering images.

Liquid phantom for investigating light propagation through layered diffusive media.

A liquid phantom for investigating light propagation through layered diffusive media is described. The diffusive medium is an aqueous suspension of calibrated scatterers and absorbers. A thin membrane separates layers with different optical properties. Experiments showed that a material with scattering properties should be used for the membrane to avoid the perturbation due to the guided propagation that occurs through a transparent layer. Examples of measurements on a three-layered medium are reported both in the cw and in the time domain.

In vivo optical characterization of human tissues from 610 to 1010 nm by time-resolved reflectance spectroscopy.

A fully automated system for time-resolved reflectance spectroscopy based on tunable mode-locked laser sources and on time-correlated single-photon counting for the detection of time-resolved reflectance data was applied to the evaluation of the optical properties of biological tissues (arm, abdomen and forehead) in vivo from 610 to 1010 nm. The scattering decreases progressively with increasing wavelength, while the absorption line shapes show the typical spectral features of the principal tissue components (haemoglobin, water and lipid), with different weights depending on the tissue type. The best fit of the absorption spectra measured in vivo with the spectra of the pure constituents yielded information on the percentage composition of the different tissues. The interpretation of transport scattering spectra with Mie theory provided information on tissue structure.