Time-domain Diffuse Correlation Spectroscopy Research Articles

Time-domain diffuse correlation spectroscopy at large source detector separation for cerebral blood flow recovery

Time-domain diffuse correlation spectroscopy (td-DCS) enables the depth discrimination in tissue’s blood flow recovery, considering the fraction of photons detected with higher time of flight (TOF) and longer pathlength through the tissue. However, the recovery result depends on factors such as the instrument response function (IRF), analyzed TOF gate start time, gate width and the source-detector separation (SDS). In this research we evaluate the performance of the td-DCS technique at three SDSs of 1.5, 2 and 2.5 cm to recover cerebral blood flow (CBF). To do that we presented comprehensive characterization of the td-DCS system through a series of phantom experiments. First by quality metrices such as coefficient of variation and contrast-to-noise ratios, we identified optimal time gate(s) of the TOF to extract dynamics of particles. Then using sensitivity metrices, each SDS ability to detect dynamics of particles in superficial and deeper layer was evaluated. Finally, td-DCS at each SDS was tested on healthy volunteers during cuff occlusion test and breathing tasks. According to phantom measurements, the sensitivity to estimate perfusion within the deep layer located at depth of 1.5 cm from the surface can be increased more than two times when the SDS increases from 1.5 cm to 2.5 cm.

Assessment of power spectral density of microvascular hemodynamics in skeletal muscles at very low and low-frequency via near-infrared diffuse optical spectroscopies.

In this work, we used a hybrid time domain near-infrared spectroscopy (TD-NIRS) and diffuse correlation spectroscopy (DCS) device to retrieve hemoglobin and blood flow oscillations of skeletal muscle microvasculature. We focused on very low (VLF) and low-frequency (LF) oscillations (i.e., frequency lower than 0.145 Hz), that are related to myogenic, neurogenic and endothelial activities. We measured power spectral density (PSD) of blood flow and hemoglobin concentration in four muscles (thenar eminence, plantar fascia, sternocleidomastoid and forearm) of 14 healthy volunteers to highlight possible differences in microvascular hemodynamic oscillations. We observed larger PSDs for blood flow compared to hemoglobin concentration, in particular in case of distal muscles (i.e., thenar eminence and plantar fascia). Finally, we compared the PSDs measured on the thenar eminence of healthy subjects with the ones measured on a septic patient in the intensive care unit: lower power in the endothelial-dependent frequency band, and larger power in the myogenic ones were observed in the septic patient, in accordance with previous works based on laser doppler flowmetry.

Fast time-domain diffuse correlation spectroscopy with superconducting nanowire single-photon detector: system validation and in vivo results

Time-domain diffuse correlation spectroscopy (TD-DCS) has been introduced as an advancement of the “classical” continuous wave DCS (CW-DCS) allowing one to not only to measure depth-resolved blood flow index (BFI) but also to extract optical properties of the measured medium without using any additional diffuse optics technique. However, this method is a photon-starved technique, specially when considering only the late photons that are of primary interest which has limited its in vivo application. In this work, we present a TD-DCS system based on a superconducting nanowire single-photon detector (SNSPD) with a high quantum efficiency, a narrow timing response, and a negligibly low dark count noise. We compared it to the typically used single-photon avalanche diode (SPAD) detector. In addition, this system allowed us to conduct fast in vivo measurements and obtain gated pulsatile BFI on the adult human forehead.

Numerical approach to quantify depth-dependent blood flow changes in real-time using the diffusion equation with continuous-wave and time-domain diffuse correlation spectroscopy.

Diffuse correlation spectroscopy (DCS) is a non-invasive optical technique that can measure brain perfusion by quantifying temporal intensity fluctuations of multiply scattered light. A primary limitation for accurate quantitation of cerebral blood flow (CBF) is the fact that experimental measurements contain information about both extracerebral scalp blood flow (SBF) as well as CBF. Separating CBF from SBF is typically achieved using multiple source-detector channels when using continuous-wave (CW) light sources, or more recently with use of time-domain (TD) techniques. Analysis methods that account for these partial volume effects are often employed to increase CBF contrast. However, a robust, real-time analysis procedure that can separate and quantify SBF and CBF with both traditional CW and TD-DCS measurements is still needed. Here, we validate a data analysis procedure based on the diffusion equation in layered media capable of quantifying both extra- and cerebral blood flow in the CW and TD. We find that the model can quantify SBF and CBF coefficients with less than 5% error compared to Monte Carlo simulations using a 3-layered brain model in both the CW and TD. The model can accurately fit data at a rate of <10 ms for CW data and <250 ms for TD data when using a least-squares optimizer.

Functional Time Domain Diffuse Correlation Spectroscopy.

Time-domain diffuse correlation spectroscopy (TD-DCS) offers a novel approach to high-spatial resolution functional brain imaging based on the direct quantification of cerebral blood flow (CBF) changes in response to neural activity. However, the signal-to-noise ratio (SNR) offered by previous TD-DCS instruments remains a challenge to achieving the high temporal resolution needed to resolve perfusion changes during functional measurements. Here we present a next-generation optimized functional TD-DCS system that combines a custom 1,064 nm pulse-shaped, quasi transform-limited, amplified laser source with a high-resolution time-tagging system and superconducting nanowire single-photon detectors (SNSPDs). System characterization and optimization was conducted on homogenous and two-layer intralipid phantoms before performing functional CBF measurements in six human subjects. By acquiring CBF signals at over 5 Hz for a late gate start time of the temporal point spread function (TPSF) at 15 mm source-detector separation, we demonstrate for the first time the measurement of blood flow responses to breath-holding and functional tasks using TD-DCS.

Development of a Monte Carlo-wave model to simulate time domain diffuse correlation spectroscopy measurements from first principles.

.Significance: Diffuse correlation spectroscopy (DCS) is an optical technique that measures blood flow non-invasively and continuously. The time-domain (TD) variant of DCS, namely, TD-DCS has demonstrated a potential to improve brain depth sensitivity and to distinguish superficial from deeper blood flow by utilizing pulsed laser sources and a gating strategy to select photons with different pathlengths within the scattering tissue using a single source–detector separation. A quantitative tool to predict the performance of TD-DCS that can be compared with traditional continuous wave DCS (CW-DCS) currently does not exist but is crucial to provide guidance for the continued development and application of these DCS systems.Aims: We aim to establish a model to simulate TD-DCS measurements from first principles, which enables analysis of the impact of measurement noise that can be utilized to quantify the performance for any particular TD-DCS system and measurement geometry.Approach: We have integrated the Monte Carlo simulation describing photon scattering in biological tissue with the wave model that calculates the speckle intensity fluctuations due to tissue dynamics to simulate TD-DCS measurements from first principles.Results: Our model is capable of simulating photon counts received at the detector as a function of time for both CW-DCS and TD-DCS measurements. The effects of the laser coherence, instrument response function, detector gate delay, gate width, intrinsic noise arising from speckle statistics, and shot noise are incorporated in the model. We have demonstrated the ability of our model to simulate TD-DCS measurements under different conditions, and the use of our model to compare the performance of TD-DCS and CW-DCS under a few typical measurement conditions.Conclusion: We have established a Monte Carlo-Wave model that is capable of simulating CW-DCS and TD-DCS measurements from first principles. In our exploration of the parameter space, we could not find realistic measurement conditions under which TD-DCS outperformed CW-DCS. However, the parameter space for the optimization of the contrast to noise ratio of TD-DCS is large and complex, so our results do not imply that TD-DCS cannot indeed outperform CW-DCS under different conditions. We made our code available publicly for others in the field to find use cases favorable to TD-DCS. TD-DCS also provides a promising way to measure deep brain tissue dynamics using a short source–detector separation, which will benefit the development of technologies including high density DCS systems and image reconstruction using a limited number of source–detector pairs.

Optimization of time domain diffuse correlation spectroscopy parameters for measuring brain blood flow.

.Significance: Time domain diffuse correlation spectroscopy (TD-DCS) can offer increased sensitivity to cerebral hemodynamics and reduced contamination from extracerebral layers by differentiating photons based on their travel time in tissue. We have developed rigorous simulation and evaluation procedures to determine the optimal time gate parameters for monitoring cerebral perfusion considering instrumentation characteristics and realistic measurement noise.Aim: We simulate TD-DCS cerebral perfusion monitoring performance for different instrument response functions (IRFs) in the presence of realistic experimental noise and evaluate metrics of sensitivity to brain blood flow, signal-to-noise ratio (SNR), and ability to reject the influence of extracerebral blood flow across a variety of time gates to determine optimal operating parameters.Approach: Light propagation was modeled on an MRI-derived human head geometry using Monte Carlo simulations for 765- and 1064-nm excitation wavelengths. We use a virtual probe with a source–detector separation of 1 cm placed in the pre-frontal region. Performance metrics described above were evaluated to determine optimal time gate(s) for different IRFs. Validation of simulation noise estimates was done with experiments conducted on an intralipid-based liquid phantom.Results: We find that TD-DCS performance strongly depends on the system IRF. Among Gaussian pulse shapes, pulse length appears to offer the best performance, at wide gates (500 ps and larger) with start times 400 and 600 ps after the peak of the TPSF at 765 and 1064 nm, respectively, for a 1-s integration time at photon detection rates seen experimentally (600 kcps at 765 nm and 4 Mcps at 1064 nm).Conclusions: Our work shows that optimal time gates satisfy competing requirements for sufficient sensitivity and sufficient SNR. The achievable performance is further impacted by system IRF with quasi-Gaussian pulse obtained using electro-optic laser shaping providing the best results.

Performance assessment of laser sources for time-domain diffuse correlation spectroscopy.

Time-domain diffuse correlation spectroscopy (TD-DCS) is an emerging optical technique that enables noninvasive measurement of microvascular blood flow with photon path-length resolution. In TD-DCS, a picosecond pulsed laser with a long coherence length, adequate illumination power, and narrow instrument response function (IRF) is required, and satisfying all these features is challenging. To this purpose, in this study we characterized the performance of three different laser sources for TD-DCS. First, the sources were evaluated based on their emission spectrum and IRF. Then, we compared the signal-to-noise ratio and the sensitivity to velocity changes of scattering particles in a series of phantom measurements. We also compared the results for in vivo measurements, performing an arterial occlusion protocol on the forearm of three adult subjects. Overall, each laser has the potential to be successfully used both for laboratory and clinical applications. However, we found that the effects caused by the IRF are more significant than the effect of a limited temporal coherence.

Time Domain Diffuse Correlation Spectroscopy for Detecting Human Brain Function: Optimize System on Real Experimental Conditions by Simulation Method

In order to achieve high-sensitivity time-domain diffuse correlation spectroscopy (TD-DCS) measurement of functional changes in cerebral blood flow, this study applied simulation methods to optimize the TD-DCS system under real experimental conditions (including the consideration of the effects of finite coherence length L <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">C</sub> and non-ideal instrument response function IRF). Under a real experimental condition where the incident power is 75 mW, the source-detector distance is 1.0 cm, and the full width at half maxima of the IRF is 160 ps, we used simulation experiments to investigate the relationship between the contrast of the intensity autocorrelation function (g <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> ) in two brain functional states (i.e., baseline and activation) and TD-DCS system parameters (including L <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">C</sub> , IRF, source-detector distance, gate opening time and gate width).Our simulation results show that both longer L <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">C</sub> and longer integration time are beneficial to a more sensitive detection. With a fixed L <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">C</sub> and integration time, the optimal parameters of gate opening time is 800 ps (relative to the peak time of IRF), and gate width is equal to or larger than 800 ps. This study may be useful for guiding the sensitive measurement of human brain functions (e.g., changes in cerebral blood flow) using the TD-DCS technology.

Time-domain diffuse correlation spectroscopy (TD-DCS) for noninvasive, depth-dependent blood flow quantification in human tissue in vivo

Monitoring of human tissue hemodynamics is invaluable in clinics as the proper blood flow regulates cellular-level metabolism. Time-domain diffuse correlation spectroscopy (TD-DCS) enables noninvasive blood flow measurements by analyzing temporal intensity fluctuations of the scattered light. With time-of-flight (TOF) resolution, TD-DCS should decompose the blood flow at different sample depths. For example, in the human head, it allows us to distinguish blood flows in the scalp, skull, or cortex. However, the tissues are typically polydisperse. So photons with a similar TOF can be scattered from structures that move at different speeds. Here, we introduce a novel approach that takes this problem into account and allows us to quantify the TOF-resolved blood flow of human tissue accurately. We apply this approach to monitor the blood flow index in the human forearm in vivo during the cuff occlusion challenge. We detect depth-dependent reactive hyperemia. Finally, we applied a controllable pressure to the human forehead in vivo to demonstrate that our approach can separate superficial from the deep blood flow. Our results can be beneficial for neuroimaging sensing applications that require short interoptode separation.

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.

Corrections to "Portable System for Time-Domain Diffuse Correlation Spectroscopy".

Corrections to "Portable System for Time-Domain Diffuse Correlation Spectroscopy".

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.

Portable System for Time-Domain Diffuse Correlation Spectroscopy.

We introduce a portable system for clinical studies based on time-domain diffuse correlation spectroscopy (DCS). After evaluating different lasers and detectors, the final system is based on a pulsed laser with about 550 ps pulsewidth, a coherence length of 38 mm, and two types of single-photon avalanche diodes (SPAD). The higher efficiency of the red-enhanced SPAD maximizes detection of the collected light, increasing the signal-to-noise ratio, while the better timing response of the CMOS SPAD optimizes the selection of late photons and increases spatial resolution. We discuss component selection and performance, and we present a full characterization of the system, measurement stability, a phantom-based validation study, and preliminary in vivo results collected from the forearms and the foreheads of four healthy subjects. With this system, we are able to resolve blood flow changes 1 cm below the skin surface with improved depth sensitivity and spatial resolution with respect to continuous wave DCS.

Time domain diffuse correlation spectroscopy: modeling the effects of laser coherence length and instrument response function.

Diffuse correlation spectroscopy (DCS) is an optical technique that non-invasively quantifies an index of blood flow (BFi) by measuring the temporal autocorrelation function of the intensity fluctuations of light diffusely remitted from the tissue. Traditional DCS measurements use continuous wave (CW) lasers with coherence lengths longer than the photon path lengths in the sample to ensure that the diffusely remitted light is coherent and generates a speckle pattern. Recently, we proposed time domain DCS (TD-DCS) to allow measurements of the speckle fluctuations for specific path lengths of light through the tissue, which has the distinct advantage of permitting an analysis of selected long path lengths of light to improve the depth sensitivity of the measurement. However, compared to CW-DCS, factors including the instrument response function (IRF), the detection gate width, and the finite coherence length need to be considered in the model analysis of the experimental data. Here we present a TD-DCS model describing how the intensity autocorrelation functions measured for different path lengths of light depend on the coherence length, pulse width of the laser, detection gate width, IRF, BFi, and optical properties of the scattering sample. Predictions of the model are compared with experimental results using a homogeneous liquid phantom sample that mimics human tissue optical properties. The BFis obtained from the TD-DCS model for different path lengths of light agree with the BFi obtained from CW-DCS measurements, while the standard simplified model underestimates the BFi by a factor of ∼2. This Letter establishes the theoretical foundation of the TD-DCS technique and provides guidance for future BFi measurements in tissue.

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.

Using a simulation approach to optimize time-domain diffuse correlation spectroscopy measurement on human head.

Time-domain diffuse correlation spectroscopy (TD-DCS) has been recently proposed to improve detection of deep blood flow dynamics in a biological tissue, such as human brain. To obtain a high sensitive measurement, several experimental parameters such as the source-detector (SD) distance, gate opening time, and width need to be considered and optimized. We use a simulation approach to optimize these parameters based on Monte Carlo computations using a realistic human head model. Two cortical regions are investigated including the frontal and temporal lobes. SD distance ranging from 0 to 45mm, gate opening time from 400 to 1000ps, and gate width from 50 to 3000ps are considered. The goal is to find out the optimal combinations of these parameters by which the higher contrast measurement on the cortical dynamics can be achieved. The simulations show that with an acceptable input power of light, the combinations of SD distance ranging from 0 to 15mm, gate opening time at 700 to 800ps, and gate width of 800ps are optimal for achieving higher contrast measurement on the cortical dynamics. The simulation approach and results are helpful for the optimization of TD-DCS experimental design focused on brain functional detection.

Analytical models for time-domain diffuse correlation spectroscopy for multi-layer and heterogeneous turbid media.

A novel approach for time-domain diffuse correlation spectroscopy (TD-DCS) has been recently proposed, which has the unique advantage by simultaneous measurements of optical and dynamical properties in a scattering medium. In this study, analytical models for calculating the time-resolved electric-field autocorrelation function is presented for a multi-layer turbid sample, as well as a semi-infinite medium embedded with a small dynamic heterogeneity. To verify the analytical models, we used Monte Carlo simulations, which demonstrated that the theoretical prediction for the time-resolved autocorrelation function was highly consistent with the Monte Carlo simulation, validating the proposed analytical models. Using these analytical models, we also showed that TD-DCS has a higher sensitivity compared to conventional continuous-wave (CW) DCS for detecting the deeper dynamics. The presented analytical models and simulations can be utilized for quantification of optical and dynamical properties from future TD-DCS experimental data as well as for optimization of the experimental design to achieve maximum contrast for deep tissue dynamics.

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.