Source-detector Separation Research Articles

Effects of the instrument response function and the gate width in time-domain diffuse correlation spectroscopy: model and validations.

Time-domain diffuse correlation spectroscopy (TD-DCS) is an emerging noninvasive optical technique with the potential to resolve blood flow (BF) and optical coefficients (reduced scattering and absorption) in depth. Here, we study the effects of finite temporal resolution and gate width in a realistic TD-DCS experiment. We provide a model for retrieving the BF from gated intensity autocorrelations based on the instrument response function, which allows for the use of broad time gates. This, in turn, enables a higher signal-to-noise ratio that is critical for in vivo applications. In numerical simulations, the use of the proposed model reduces the error in the estimated late gate BF from 34% to 3%. Simulations are also performed for a wide set of optical properties and source-detector separations. In a homogeneous phantom experiment, the discrepancy between later gates BF index and ungated BF index is reduced from 37% to 2%. This work not only provides a tool for data analysis but also physical insights, which can be useful for studying and optimizing the system performance.

Dual Layered Models of Light Scattering in the Near Infrared B: Experimental Results with a Phantom.

Intralipid emulsion is often used as optical model substance to mimic living tissue's strong scattering properties. As such it is of considerable importance to utilize realistic parameters for any type of simulation or calculation in context of Near Infrared Spectroscopy. We determined optical characteristics of diluted Intralipid solutions at often used, realistic volume concentrations ρil and at two wavelengths (780nm and 850nm) in a simple phantom setup featuring multiple sensors with different source-detector-separation (SDS) and penetration depths d. Both, phantom experiments and MC simulation showed qualitatively similar results and demonstrated the influence of the three major NIRS factors, namely the penetrated layer depth (d), the Intralipid concentration ρil and the source-detector separation (SDS). The results demonstrated that light reaching the detectors is inversely proportional to ρil and d. It corroborates the need for differential measurements with at least two SDS to account for superficial large angle scattering.

Estimating the Dependence of Differential Pathlength Factor on Blood Volume and Oxygen Saturation using Monte Carlo method.

Differential Pathlength Factor (DPF) is a vital parameter for the Beer-Lambert law based calculations in estimating tissue perfusion using non-invasive optical techniques. A significant error in the measured concentration of oxyhemoglobin and deoxyhemoglobin has been reported due to the usage of wrong DPF values. The dependence of DPF on blood oxygen saturation and blood volume has never been studied earlier. In this work, a Monte Carlo model of perfused skin tissue was developed and executed at 660 nm and 940 nm optical wavelengths at a reflectance geometry. DPFs were simulated through 1-10 mm source detector separations at different blood volumes and oxygen saturations. Results showed higher DPFs at lower wavelengths and considerable variation with blood volume and oxygen saturation.

A Versatile Setup for Time-Resolved Functional Near Infrared Spectroscopy Based on Fast-Gated Single-Photon Avalanche Diode and on Four-Wave Mixing Laser

In this paper, a time-domain fast gated near-infrared spectroscopy system is presented. The system is composed of a fiber-based laser providing two pulsed sources and two fast gated detectors. The system is characterized on phantoms and was tested in vivo, showing how the gating approach can improve the contrast and contrast-to-noise-ratio for detection of absorption perturbation inside a diffusive medium, regardless of source-detector separation.

Comparison of Lipid and Water Contents by Time-domain Diffuse Optical Spectroscopy and Dual-energy Computed Tomography in Breast Cancer Patients

We previously compared time-domain diffuse optical spectroscopy (TD-DOS) with magnetic resonance imaging (MRI) using various water/lipid phantoms. However, it is difficult to conduct similar comparisons in the breast, because of measurement differences due to modality-dependent differences in posture. Dual-energy computed tomography (DECT) examination is performed in the same supine position as a TD-DOS measurement. Therefore, we first verified the accuracy of the measured fat fraction of fibroglandular tissue in the normal breast on DECT by comparing it with MRI in breast cancer patients (n = 28). Then, we compared lipid and water signals obtained in TD-DOS and DECT from normal and tumor-tissue regions (n = 16). The TD-DOS breast measurements were carried out using reflectance geometry with a source–detector separation of 3 cm. A semicircular region of interest (ROI), with a transverse diameter of 3 cm and a depth of 2 cm that included the breast surface, was set on the DECT image. Although the measurement area differed between the modalities, the correlation coefficients of lipid and water signals between TD-DOS and DECT were rs = 0.58 (p < 0.01) and rs = 0.90 (p < 0.01), respectively. These results indicate that TD-DOS captures the characteristics of the lipid and water contents of the breast.

Validation of a Second-Generation Near-Infrared Spectroscopy Monitor in Children With Congenital Heart Disease.

Cerebral oximetry using near-infrared spectroscopy is a noninvasive optical technology to detect cerebral hypoxia-ischemia and develop interventions to prevent and ameliorate hypoxic brain injury. Cerebral oximeters are calibrated and validated by comparison of the near-infrared spectroscopy-measured cerebral O2 saturation (SctO2) to a "field" or reference O2 saturation (REF CX) calculated as a weighted average from arterial and jugular bulb oxygen saturations. In this study, we calibrated and validated the second-generation, 5 wavelength, FORE-SIGHT Elite with the medium sensor (source-detector separation 12 and 40 mm) for measurement of SctO2 in children with congenital heart disease. After institutional review board approval and written informed consent, 63 children older than 1 month and ≥2.5 kg scheduled for cardiac catheterization were enrolled. Self-adhesive FORE-SIGHT Elite medium sensors were placed on the right and left sides of the forehead. Blood samples for calculation of REF CX were drawn simultaneously from the aorta or femoral artery and the jugular bulb before (T1) and shortly after (T2) baseline hemodynamic measurements. FORE-SIGHT Elite SctO2 measurements were compared to the REF CX (REF CX = [0.3 SaO2] + [0.7 SjbO2]) using Deming regression, least squares linear regression, and Bland-Altman analysis. Sixty-one subjects (4.5 [standard deviation 4.4] years of age; 17 [standard deviation 13] kg, male 56%) completed the study protocol. Arterial oxygen saturation ranged from 64.7% to 99.1% (median 96.0%), jugular bulb venous oxygen saturation from 34.1% to 88.1% (median 68.2%), the REF CX from 43.8% to 91.4% (median 76.9%), and the SctO2 from 47.8% to 90.8% (median 76.3%). There was a high degree of correlation in SctO2 between the right and left sensors at a given time point (within subject between sensor correlation r = 0.91 and 95% confidence interval [CI], 0.85-0.94) or between T1 and T2 for the right and left sensors (replicates, within subject between time point correlation r = 0.95 and 95% CI, 0.92-0.96). By Deming regression, the estimated slope was 0.966 (95% CI, 0.786-1.147; P = .706 for testing against null hypothesis of slope = 1) with a y intercept of 2.776 (95% CI, -11.102 to 16.654; P = .689). The concordance correlation coefficient was 0.873 (95% CI, 0.798-0.922). Bland-Altman analysis for agreement between SctO2 and REF CX that accounted for repeated measures (both in times and sensors) found a bias of -0.30% (95% limits of agreement: -10.56% to 9.95%). This study calibrated and validated the FORE-SIGHT Elite tissue oximeter to accurately measure SctO2 in pediatric patients with the medium sensor.

Monte Carlo Analysis of Optical Interactions in Reflectance and Transmittance Finger Photoplethysmography.

Photoplethysmography (PPG) is a non-invasive photometric technique that measures the volume changes in arterial blood. Recent studies have reported limitations in developing and optimising PPG-based sensing technologies due to unavailability of the fundamental information such as PPG-pathlength and penetration depth in a certain region of interest (ROI) in the human body. In this paper, a robust computational model of a dual wavelength PPG system was developed using Monte Carlo technique. A three-dimensional heterogeneous volume of a specific ROI (i.e., human finger) was exposed at the red (660 nm) and infrared (940 nm) wavelengths in the reflectance and transmittance modalities of PPG. The optical interactions with the individual pulsatile and non-pulsatile tissue-components were demonstrated and the optical parameters (e.g., pathlength, penetration depth, absorbance, reflectance and transmittance) were investigated. Results optimised the source-detector separation for a reflectance finger-PPG sensor. The analysis with the recorded absorbance, reflectance and transmittance confirmed the maximum and minimum impact of the dermis and bone tissue-layers, respectively, in the formation of a PPG signal. The results presented in the paper provide the necessary information to develop PPG-based transcutaneous sensors and to understand the origin of the ac and dc components of the PPG signal.

Diffuse reflectance spectroscopy-enhanced drill for bone boundary detection.

Intramedullary nailing is a routine orthopedic procedure used for treating fractures of femoral or tibial shafts. A critical part of this procedure involves the drilling of pilot holes in both ends of the bone for the placement of the screws that will secure the IM rod to sections of the fractured bone. This step introduces a risk of soft tissue damage because the drill bit, if not stopped in time, can transverse the bone-tissue boundary into the overlying muscle, causing unnecessary injury and prolonging healing time due to periosteum damage. In this respect, detecting the bone-tissue boundary before break-through can reduce the risks and complications associated with intramedullary nailing. Hence, in the present study, a two-wavelength diffuse reflectance spectroscopy technique was integrated into a surgical drill to optically detect bone-tissue boundary and automatically trigger the drill to stop. Furthermore, Monte-Carlo simulations were used to estimate the maximum distance from within the bone at which the bone-tissue boundary could be detected using DRS. The simulation results estimated that the detection distance, termed the "look-ahead-distance" was ∼1.5 mm for 1.3 mm source-detector fiber separation. Experimental measurements with 1.3 mm source-detector fiber separation showed that the look-ahead-distance was in the order of 250 µm in experiments with set drill rate and in the range of 1 mm in experiments where the holes were drilled by hand. Despite this difference, the automated DRS enhanced drill successfully detected the approaching bone tissue boundary when tested on samples of bovine femur and muscle tissue.

Next-generation frequency domain diffuse optical imaging systems using silicon photomultipliers

Diffuse optical imaging of biological tissue is a well-established methodology used to measure functional information from intrinsic contrast due to hemoglobin, water, and lipid. This information is exploited in frequency domain diffuse optical spectroscopy (FD-DOS) systems, which have been used to investigate chemotherapy response, optical mammography, and brain imaging. FD-DOS depth sensitivity and dynamic range are typically constrained by photodetector sensitivity. Here we present FD-DOS utilizing a silicon photomultiplier (SiPM) detector that has a higher signal-to-noise ratio (SNR) compared to an avalanche photodiode (APD), and thus enables extended source-detector (S/D) separations and increased depth penetration. We find the SiPM to have 10-30dB greater SNR than a comparably sized APD while detecting 1.5-2 orders of magnitude lower light levels, down to ∼4 pW at 50MHz modulation. The SiPM and APD recover optical property values of tissue-simulating phantoms within 13% agreement and are stable with 1% coefficient of variation over one hour. Finally, the SiPM is used to accurately recover optical properties in a reflectance geometry at S/D separations up to 48mm in phantoms mimicking human breast tissue.

Multi-distance frequency-domain optical measurements of coherent cerebral hemodynamics.

We report non-invasive, bilateral optical measurements on the forehead of five healthy human subjects, of 0.1 Hz oscillatory hemodynamics elicited either by cyclic inflation of pneumatic thigh cuffs, or by paced breathing. Optical intensity and the phase of photon-density waves were collected with frequency-domain near-infrared spectroscopy at seven source-detector distances (11-40 mm). Coherent hemodynamic oscillations are represented by phasors of oxyhemoglobin (O) and deoxyhemoglobin (D) concentrations, and by the vector D/O that represents the amplitude ratio and phase difference of D and O. We found that, on average, the amplitude ratio (|D/O|) and the phase difference (∠(D/O)) obtained with single-distance intensity at 11-40 mm increase from 0.1 and −330°, to 0.2 and −200°, respectively. Single-distance phase and the intensity slope featured a weaker dependence on source-detector separation, and yielded |D/O| and ∠(D/O) values of about 0.5 and −200°, respectively, at distances greater than 20 mm. The key findings are: (1) single-distance phase and intensity slope are sensitive to deeper tissue compared to single-distance intensity; (2) deeper tissue hemodynamic oscillations, which more closely represent the brain, feature D and O phasors that are consistent with a greater relative flow-to-volume contributions in brain tissue compared to extracerebral, superficial tissue.

Toward Quantitative Near Infrared Brain Functional Imaging: Lock-In Photon Counting Instrumentation Combined With Tomographic Reconstruction

It is well acknowledged that the functional near-infrared spectroscopic (fNIRS) imaging of brain functions can be quantitatively enhanced by diffuse optical tomography (DOT). Unlike the widely-used conventional optical topography (optical mapping), an fNIRS-DOT instrument needs to possess both high sensitivity and large dynamic-range so that measurements at multiple source-detector separations are reliably and synchronously collected for improved depth-resolution, quantitation, and superficial signal reduction, the performances particularly crucial to the occipital cortex probing. For the goal, we implemented a novel 3-wavelength, 240-channel (20 sources and 12 detectors) continuous-wave fNIRS-DOT instrument. The system features the square-wave modulation lock-in photon-counting scheme that combines the multi-channel parallelization of the lock-in detection, the ultra-high sensitivity, and unprecedented dynamic-range of the photon-counting technique, as well as the reduced complexity of the hardware architecture. We have systematically investigated the key specifications of the instrument such as the detection linearity, stability, channel crosstalks and so on, under the practically-viable conditions of the incident power and signal-to-noise ratio, and accordingly proposed wavelength-switched multiple-field illumination paradigms for both the non-overlapping and overlapping DOT measurements, respectively. Finally, DOT experiments using the semi-three-dimensional image reconstruction has been conducted on a phantom with a practically low-contrasted and deep-sit absorption target, to evaluate the overall imaging performance of the system and to demonstrate the superiority of the model-based image reconstruction over the topographical mapping.

Study on the cross-polarization method for extracting internal information of objects

In noninvasive near-infrared (NIR) noncontact measurement, a cross-polarization method is employed to eliminate undesired surface reflection and extract useful internal information. Experiments on various samples (both in vitro and in vivo) at different source-detector separations (SDSs) were conducted to investigate the effectiveness of this method. In conclusion, the cross-polarization method is proved to be effective in eliminating surface reflection as well as conducive to the measurement of objects’ internal information and this method is more suitable for scattering objects with smooth surfaces and complex interiors. Furthermore, a larger SDS can lead to a better measurement effect. This study can be a reference for tissue constituent sensing.

Depth dependence of coherent hemodynamics in the human head.

We report a near-infrared spectroscopy (NIRS) study of coherent hemodynamic oscillations measured on the human forehead at multiple source-detector distances (1 to 4cm). The physiological source of the coherent hemodynamics is arterial blood pressure oscillations at a frequency of 0.1Hz, induced by cyclic inflation (to a pressure of 200mmHg) and deflation of two thigh cuffs wrapped around the subject's thighs. To interpret our results, we use a recently developed hemodynamic model and a phasor representation of the oscillations of oxyhemoglobin, deoxyhemoglobin, and total hemoglobin concentrations in the tissue (phasors O, D, and T, respectively). The increase in the phase angle between D and O at larger source-detector separations is assigned to greater flow versus volume contributions and to a stronger blood flow autoregulation in deeper tissue (brain cortex) with respect to superficial tissue (scalp and skull). The relatively constant phase lag of T versus arterial blood pressure oscillations at all source-detector distances was assigned to competing effects from stronger autoregulation and smaller arterial-to-venous contributions in deeper tissue with respect to superficial tissue. We demonstrate the application of a hemodynamic model to interpret coherent hemodynamics measured with NIRS and to assess the different nature of shallow (extracerebral) versus deep (cerebral) tissue hemodynamics.

Approaches to denoise the diffuse optical signals for tissue blood flow measurement

Various diseases are relevant to the abnormal blood flow in tissue. Diffuse correlation spectroscopy (DCS) is an emerging technology to extract the blood flow index (BFI) from light electric field temporal autocorrelation data. To account for tissue heterogeneity and irregular geometry, we developed an innovative DCS algorithm (i.e., the Nth order linear algorithm, or simply the NL algorithm) previously, in which the DCS signals are fully utilized through iterative linear regressions. Under the framework of NL algorithm, the BFI to be extracted is significantly influenced by the linear regression approach adopted. In this study, three approaches were proposed and evaluated for performing the iterative linear regressions, in order to understand what are the appropriate regression methods for BFI estimation. The three methods are least-squared minimization (L2 norm), least-absolute minimization (L1 norm) and support vector regression (SVR), where L2 norm is a conventional approach to perform linear regression. L1 norm and SVR are the approaches newly introduced here to process the DCS data. Computer simulations and the autocorrelation data collected from liquid phantom and human tissues are utilized to evaluate the three approaches. The results show that the best performance is achieved by the SVR approach in extracting the BFI values, with an error rate of 2.23% at 3.0 cm source-detector separation. The L1 norm method gives a medium error of 2.81%. In contrast, the L2 norm method leads to the largest error (3.93%) in extracting the BFI values. The outcomes derived from this study will be very helpful for the tissue blood flow measurements, which is critical for translating the DCS technology to the clinic.

Scattering-independent glucose absorption measurement using a spectrally resolved reflectance setup with specialized variable source-detector separations.

We report a novel approach for the accurate measurement of glucose absorption in turbid media using a spectrally resolved reflectance setup. Our proposed reflectance setup with specialized variable source-detector separations enables scattering-independent absorption measurement, which is critical to in vivo long-term glucose concentration monitoring. Starting from the first-order approximation of the radiative transfer equation (RTE), we developed a scattering-independent glucose absorption measurement method and then evaluated this approach by Monte Carlo simulations as well as tissue-mimicking phantom studies in which glucose concentration was accurately measured. Our study demonstrates the potential of our proposed scattering-independent absorption measurement technique as an effective tool to quantify glucose levels in turbid media, which is an important step towards future in vivo long-term glucose concentration monitoring in human subjects.

Small separation diffuse correlation spectroscopy for measurement of cerebral blood flow in rodents.

Diffuse correlation spectroscopy (DCS) has shown promise as a means to non-invasively measure cerebral blood flow in small animal models. Here, we characterize the validity of DCS at small source-detector reflectance separations needed for small animal measurements. Through Monte Carlo simulations and liquid phantom experiments, we show that DCS error increases as separation decreases, although error remains below 12% for separations > 0.2 cm. In mice, DCS measures of cerebral blood flow have excellent intra-user repeatability and strongly correlate with MRI measures of blood flow (R = 0.74, p<0.01). These results are generalizable to other DCS applications wherein short-separation reflectance geometries are desired.

Quantitative subsurface imaging in strongly scattering media.

We present a method to obtain quantitatively accurate images of small obstacles or inhomogeneities situated near the surface of a strongly scattering medium. The method uses time-resolved measurements of backscattered light to form the images. Using the asymptotic solution of the radiative transfer equation for this problem, we determine that the key information content in measurements is modeled by a diffusion approximation that is valid for small source-detector distances, and shallow penetration depths. We simplify this model further by linearizing the effect of the inhomogeneities about the known background optical properties using the Born approximation. The resulting model is used in a two-stage imaging algorithm. First, the spatial location of the inhomogeneities are determined using a modification of the multiple signal classification (MUSIC) method. Using those results, we then determine the quantitative values of the inhomogeneities through a least-squares approximation. We find that this two-stage method is most effective for reconstructing a sequence of one-dimensional images along the penetration depth corresponding to null source-detector separations rather than simultaneously using measurements over several source-detector distances. This method is limited to penetration depths and distances between boundary measurements on the order of the scattering mean-free path.

Sampling depth of a diffuse reflectance spectroscopy probe for in-vivo physiological quantification of murine subcutaneous tumor allografts.

Diffuse reflectance spectroscopy (DRS) is a probe-based spectral biopsy technique used in cancer studies to quantify tissue reduced scattering (μs') and absorption (μa) coefficients and vary in source-detector separation (SDS) to fine-tune sampling depth. In subcutaneous murine tumor allografts or xenografts, a key design requirement is ensuring that the source light interrogates past the skin layer into the tumor without significantly sacrificing signal-to-noise ratio (target of ≥15 dB). To resolve this requirement, a DRS probe was designed with four SDSs (0.75, 2.00, 3.00, and 4.00mm) to interrogate increasing tissue volumes between 450 and 900nm. The goal was to quantify percent errors in extracting μa and μs', and to quantify sampling depth into subcutaneous Balb/c-CT26 colon tumor allografts. Using an optical phantom-based experimental method, lookup-tables were constructed relating μa,μs', diffuse reflectance, and sampling depth. Percent errors were <10 % and 5% for extracting μa and μs', respectively, for all SDSs. Sampling depth reached up to 1.6mm at the first Q-band of hemoglobin at 542nm, the key spectral region for quantifying tissue oxyhemoglobin concentration. This work shows that the DRS probe can accurately extract optical properties and the resultant physiological parameters such as total hemoglobin concentration and tissue oxygen saturation, from sufficient depth within subcutaneous Balb/c-CT26 colon tumor allografts. Methods described here can be generalized for other murine tumor models. Future work will explore the feasibility of the DRS in quantifying volumetric tumor perfusion in response to anticancer therapies.

Effects of capsule on surface diffuse reflectance spectroscopy of the subcapsular parenchyma of a solid organ.

We hypothesize that the capsular optical properties and thickness combined affect how accurate the diffuse reflectance on the surface of a capsular solid organ represents that on the subcapsular parenchyma. Monte Carlo simulations on two-layer geometries evaluated how a thin superficial layer with the thickness from 10 to 1000 μm affected the surface diffuse reflectance over a source-detector separation spanning 0.01 to 10mm. The simulations represented the superficial layer presenting various contrasts concerning refractive index, anisotropy factor, absorption coefficient, and reduced scattering coefficient, versus those of the subsurface main medium. An analytical approach modeled the effects of the superficial layer of various thicknesses and optical properties on diffuse reflectance. Diffuse reflectance spectroscopy was performed ex vivo on 10 fresh human livers and 9 fresh human kidneys using a surface probe with a 3-mm source-detector separation. The difference of the device-specific diffuse reflectance on the organ between with the capsule and without the capsule has significantly greater spectral variation in the kidney than in the liver. The significantly greater spectral deviation of surface diffuse reflectance between with and without the capsule in the kidney than in the liver was analytically accountable by considering the much thicker capsule of the kidney than of the liver.

Investigating optical path and differential pathlength factor in reflectance photoplethysmography for the assessment of perfusion.

Photoplethysmography (PPG) is an optical noninvasive technique with the potential for assessing tissue perfusion. The relative time-change in the concentration of oxyhemoglobin and deoxyhemoglobin in the blood can be derived from DC part of the PPG signal. However, the absolute concentration cannot be determined due to the inadequate data on PPG optical paths. The optical path and differential pathlength factor (DPF) for PPG at red (660nm) and infrared (880nm) wavelengths were investigated using a heterogeneous Monte Carlo model of the human forearm. Using the simulated DPFs, the absolute time-change in concentrations were determined from PPG signals recorded from the same tissue site. Results were compared with three conditions of approximated DPFs. Results showed the variation of the optical-path and DPF with different wavelengths and source-detector separations. Approximations resulted in significant errors, for example, using NIRS DPF in PPG led to "cross talk" of -0.4297 and 0.060 and an error of 15.16% to 25.18%. Results confirmed the feasibility of using the PPG (DC) for the assessment of tissue perfusion. The study also identified the inappropriateness of the assumption that DPF is independent of wavelength or source-detector separations and set the platform for further studies on investigating optical pathlengths and DPF in PPG.