Yves Bérubé-Lauzière

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.

A multi-view time-domain non-contact diffuse optical tomography scanner with dual wavelength detection for intrinsic and fluorescence small animal imaging.

We present a non-contact diffuse optical tomography (DOT) scanner with multi-view detection (over 360°) for localizing fluorescent markers in scattering and absorbing media, in particular small animals. It relies on time-domain detection after short pulse laser excitation. Ultrafast time-correlated single photon counting and photomultiplier tubes are used for time-domain measurements. For light collection, seven free-space optics non-contact dual wavelength detection channels comprising 14 detectors overall are placed around the subject, allowing the measurement of time point-spread functions at both excitation and fluorescence wavelengths. The scanner is endowed with a stereo camera pair for measuring the outer shape of the subject in 3D. Surface and DOT measurements are acquired simultaneously with the same laser beam. The hardware and software architecture of the scanner are discussed. Phantoms are used to validate the instrument. Results on the localization of fluorescent point-like inclusions immersed in a scattering and absorbing object are presented. The localization algorithm relies on distance ranging based on the measurement of early photons arrival times at different positions around the subject. This requires exquisite timing accuracy from the scanner. Further exploiting this capability, we show results on the effect of a scattering hetereogenity on the arrival time of early photons. These results demonstrate that our scanner provides all that is necessary for reconstructing images of small animals using full tomographic reconstruction algorithms, which will be the next step. Through its free-space optics design and the short pulse laser used, our scanner shows unprecedented timing resolution compared to other multi-view time-domain scanners.

Fat emulsions as diffusive reference standards for tissue simulating phantoms

Intralipid 20% was recently suggested as a diffusive reference standard for tissue simulating phantoms. In this work, we extend previously obtained results to other fat emulsions, specifically Intralipid 10%, Intralipid 30%, Lipovenoes 10%, Lipovenoes 10% PhosphoLipid Reduced, Lipovenoes 20%, Lipofundin S 10%, and Lipofundin S 20%. Of particular importance for practical applications, our measurements carried out at a wavelength of 751 nm show the following features. First, these products show high stability and small batch-to-batch variations in their diffusive optical properties, similar to Intralipid 20%. Second, the absorption coefficient of Intralipid, Lipovenoes, and Lipofundin S are very similar and their measured values are within the experimental errors; moreover the reduced scattering coefficient of Intralipid 20%, Lipovenoes 20%, and Lipofundin S 20% are similar and their measured values are within 5%. Third, the reduced scattering coefficient of Intralipid 10% and Intralipid 30% can be scaled from that of Intralipid 20% with an error of 9% and 2%, respectively. A similar scaling property is valid for Lipovenoes and Lipofundin S. We have verified that this scaling property depends on the composition of the fat emulsions: If the ingredients exactly scale with the concentration then the reduced scattering coefficient almost exactly scale as well.

Light propagation from fluorescent probes in biological tissues by coupled time-dependent parabolic simplified spherical harmonics equations

We introduce a system of coupled time-dependent parabolic simplified spherical harmonic equations to model the propagation of both excitation and fluorescence light in biological tissues. We resort to a finite element approach to obtain the time-dependent profile of the excitation and the fluorescence light fields in the medium. We present results for cases involving two geometries in three-dimensions: a homogeneous cylinder with an embedded fluorescent inclusion and a realistically-shaped rodent with an embedded inclusion alike an organ filled with a fluorescent probe. For the cylindrical geometry, we show the differences in the time-dependent fluorescence response for a point-like, a spherical, and a spherically Gaussian distributed fluorescent inclusion. From our results, we conclude that the model is able to describe the time-dependent excitation and fluorescent light transfer in small geometries with high absorption coefficients and in nondiffusive domains, as may be found in small animal diffuse optical tomography (DOT) and fluorescence DOT imaging.

Time-domain 3D localization of fluorescent inclusions in a thick scattering medium

We introduce an improved approach in the 3D localization of discrete fluorescent inclusions in a thick scattering medium. Previously our approach provided accurate localization of a single inclusion, showing the potential for direct time-of-flight fluorescence diffuse optical tomography. Here, we localize various combinations of multiple fluorescent inclusions. We resort to time-domain (TD) detection of emitted fluorescence pulses after short pulse laser excitation. Our approach relies on a signal processing technique, dubbed numerical constant fraction discrimination (NCFD), for extracting in a stable manner the arrival time of early photons emitted by one or many fluorescent inclusions from measured time-of-flight (TOF) distributions. Our experimental set-up allows multi-view tomographic optical TD measurements over 360 degrees without contact with the medium. It uses an ultra-short pulse laser and ultra-fast time-correlated single photon counting (TCSPC) detection. Fluorescence time point-spread functions (FTPSFs) are acquired all around the phantom after laser excitation. From measured FTPSFs, the arrival time of a fluorescent wavefront at a detector position is extracted with our NCFD technique. Indocyanine green (ICG; absorption peak = 780nm, emission peak = 830nm) is used for the inclusions. Various experiments were conducted with this set-up in a stepwise fashion. First, single inclusion experiments are presented to provide background information. Second, we present results using two inclusions in a plane. Then, we move on with two inclusions located in different planes. Finally, we show results with a plurality of inclusions (>2) distributed at arbitrary positions in the medium. Using an algorithm we have developed and tested on the acquired data, we successfully achieve to locate the inclusions. Here, results are obtained for discrete inclusions. In a close future, we expect to extend our method to continuous fluorescence distributions.

High precision time-to-amplitude converter for diffuse optical tomography applications

Molecular imaging aims to better understand biochemical processes at the molecular level in living organisms. Among emerging imaging modalities, diffuse optical tomography (DOT) coupled with the use of fluorescent bio-markers proposes solutions to visualize such processes. The Universite de Sherbrooke is developing a 128-channel DOT scanner dedicated to small animal imaging. The scanner is based on ultra-fast time-resolved optical measurements using time-correlated single photon counting (TCSPC). This paper reports a preliminary design of a high resolution 4- channel time to amplitude converter (TAC) used for time of flight optical measurements, in CMOS 0.18 mum technology. The TAC achieves a 5 ps resolution in a 13 ns timing window, and has a 150 ns dead time. It includes all auxiliary electronics: D-flip-flop, current source, integrator, switches and fully balanced buffer able to drive an off-the-shelf free running 50 Msps analog to digital converter (ADC).

Time-of-flight non-contact fluorescence diffuse optical tomography with numerical constant fraction discrimination

We introduce a novel non-contact fluorescence diffuse optical tomography (FDOT) approach for localizing a fluorescent inclusion embedded in a scattering medium. It uses the time of flight of early photons arriving at several detector positions around the medium. It is a true and direct time-of-flight approach in that arrival times are converted to distance. The arrival time of early photons is found via a recently introduced numerical constant fraction discriminator applied to fluoresced photons time-of-flight distributions (fluorescence time pointspread functions (FTPSFs)). Time-correlated single photon counting and an ultrafast photon counting avalanche photodiode are used for measuring FTPSFs that form tomographic data sets. The FDOT localization algorithm proceeds in two steps. The first determines the angular position of the inclusion as the average, over projections, of angular detector positions with smallest arrival time. The second determines the inclusions radial position based on relative arrival times obtained at several detector positions within each tomographic projection relatively to a reference detector position, the latter being that of shortest arrival time in the projection. The radial position found minimizes the discrepancy between relative arrival times computed for several possible inclusion positions and relative arrival times deduced from experimental data. Two methods are presented for this.

Prospects on Time-Domain Diffuse Optical Tomography Based on Time-Correlated Single Photon Counting for Small Animal Imaging

This paper discusses instrumentation based on multiview parallel high temporal resolution (<50 ps) time-domain (TD) measurements for diffuse optical tomography (DOT) and a prospective view on the steps to undertake as regards such instrumentation to make TD-DOT a viable technology for small animal molecular imaging. TD measurements provide information-richest data, and we briefly review the interaction of light with biological tissues to provide an understanding of this. This data richness is yet to be exploited to its full potential to increase the spatial resolution of DOT imaging and to allow probing, via the fluorescence lifetime, tissue biochemical parameters, and processes that are otherwise not accessible in fluorescence DOT. TD data acquisition time is, however, the main factor that currently compromises the viability of TD-DOT. Current high temporal resolution TD-DOT scanners simply do not integrate sufficient detection channels. Based on our past experience in developing TD-DOT instrumentation, we review and discuss promising technologies to overcome this difficulty. These are single photon avalanche diode (SPAD) detectors and fully parallel highly integrated electronics for time-correlated single photon counting (TCSPC). We present experimental results obtained with such technologies demonstrating the feasibility of next-generation multiview TD-DOT therewith.

Time-resolved fluorescence measurements for diffuse optical tomography using ultrafast time-correlated single photon counting

We develop a novel approach to infer depth information about a small fluorophore-filled inclusion immersed in a scattering medium. It relies on time-resolved measurements of the time of flight distribution of emitted fluorescent photons after short pulse laser excitation. The approach uses a novel numerical constant fraction discrimination technique to assign a stable arrival time to the distributions early photons. Our experimental results show a linear relationship between these arrival times and the position of the inclusion. This approach will serve as a useful technique in fluorescence diffuse optical tomography.

A 10-Bit, 12 ps Resolution CMOS Time-to-Digital Converter Dedicated to Ultra-Fast Optical Timing Applications

This paper reports the design of a 10-bit, high-resolution time-to-digital converter (TDC) based on Vernier residues amplification which is a novelty. This TDC architecture allows the measurement of wide time intervals with high picosecond-range resolution. The key benefits of the proposed TDC are that it reduces conversion jitter and provides more design flexibility to enhance matching performances of delay cells and thus reach high conversion linearity regardless of the process technology, which is a strong aspect of the approach. Simulations results show that the TDC achieves a timing resolution of 12 ps rms in a long 12.5 ns timing window, a low core power consumption of 4.8 mW and estimated differential and integral nonlinearities (DNL and INL) of 0.73 and 2.02 LSB with a standard deviation of 0.17 and 0.94 LSB respectively. The TDC, implemented in 0.13 mm CMOS technology, occupies a total silicon area of 1.83