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.

In vivocharacterization of the optical and hemodynamic properties of the human sternocleidomastoid muscle through ultrasound-guided hybrid near-infrared spectroscopies.

Objective.In this paper, we present a detailedin vivocharacterization of the optical and hemodynamic properties of the human sternocleidomastoid muscle (SCM), obtained through ultrasound-guided near-infrared time-domain and diffuse correlation spectroscopies.Approach.A total of sixty-five subjects (forty-nine females, sixteen males) among healthy volunteers and thyroid nodule patients have been recruited for the study. Their SCM hemodynamic (oxy-, deoxy- and total hemoglobin concentrations, blood flow, blood oxygen saturation and metabolic rate of oxygen extraction) and optical properties (wavelength dependent absorption and reduced scattering coefficients) have been measured by the use of a novel hybrid device combining in a single unit time-domain near-infrared spectroscopy, diffuse correlation spectroscopy and simultaneous ultrasound imaging.Main results.We provide detailed tables of the results related to SCM baseline (i.e. muscle at rest) properties, and reveal significant differences on the measured parameters due to variables such as side of the neck, sex, age, body mass index, depth and thickness of the muscle, allowing future clinical studies to take into account such dependencies.Significance.The non-invasive monitoring of the hemodynamics and metabolism of the sternocleidomastoid muscle during respiration became a topic of increased interest partially due to the increased use of mechanical ventilation during the COVID-19 pandemic. Near-infrared diffuse optical spectroscopies were proposed as potential practical monitors of increased recruitment of SCM during respiratory distress. They can provide clinically relevant information on the degree of the patient's respiratory effort that is needed to maintain an optimal minute ventilation, with potential clinical application ranging from evaluating chronic pulmonary diseases to more acute settings, such as acute respiratory failure, or to determine the readiness to wean from invasive mechanical ventilation.

Lock-in functional near-infrared spectroscopy for measurement of the haemodynamic brain response.

Here we show a method of the lock-in amplifying near-infrared signals originating within a human brain. It implies using two 90-degree rotated source-detector pairs fixed on a head surface. Both pairs have a joint sensitivity region located towards the brain. A direct application of the lock-in technique on both signals results in amplifying common frequency components, e.g. related to brain cortex stimulation and attenuating the rest, including all components not related to the stimulation: e.g. pulse, instrumental and biological noise or movement artefacts. This is a self-driven method as no prior assumptions are needed and the noise model is provided by the interfering signals themselves. We show the theory (classical modified Beer-Lambert law and diffuse optical tomography approaches), the algorithm implementation and tests on a finite element mathematical model and in-vivo on healthy volunteers during visual cortex stimulation. The proposed hardware and algorithm complexity suit the entire spectrum of (continuous wave, frequency domain, time-resolved) near-infrared spectroscopy systems featuring real-time, direct, robust and low-noise brain activity registration tool. As such, this can be of special interest in optical brain computer interfaces and high reliability/stability monitors of tissue oxygenation.

Time-domain NIRS system based on supercontinuum light source and multi-wavelength detection: validation for tissue oxygenation studies.

We present and validate a multi-wavelength time-domain near-infrared spectroscopy (TD-NIRS) system that avoids switching wavelengths and instead exploits the full capability of a supercontinuum light source by emitting and acquiring signals for the whole chosen range of wavelengths. The system was designed for muscle and brain oxygenation monitoring in a clinical environment. A pulsed supercontinuum laser emits broadband light and each of two detection modules acquires the distributions of times of flight of photons (DTOFs) for 16 spectral channels (used width 12.5 nm / channel), providing a total of 32 DTOFs at up to 3 Hz. Two emitting fibers and two detection fiber bundles allow simultaneous measurements at two positions on the tissue or at two source-detector separations. Three established protocols (BIP, MEDPHOT, and nEUROPt) were used to quantitatively assess the system's performance, including linearity, coupling, accuracy, and depth sensitivity. Measurements were performed on 32 homogeneous phantoms and two inhomogeneous phantoms (solid and liquid). Furthermore, measurements on two blood-lipid phantoms with a varied amount of blood and Intralipid provide the strongest validation for accurate tissue oximetry. The retrieved hemoglobin concentrations and oxygen saturation match well with the reference values that were obtained using a commercially available NIRS system (OxiplexTS) and a blood gas analyzer (ABL90 FLEX), except a discrepancy occurs for the lowest amount of Intralipid. In-vivo measurements on the forearm of three healthy volunteers during arterial (250 mmHg) and venous (60 mmHg) cuff occlusions provide an example of tissue monitoring during the expected hemodynamic changes that follow previously well-described physiologies. All results, including quantitative parameters, can be compared to other systems that report similar tests. Overall, the presented TD-NIRS system has an exemplary performance evaluated with state-of-the-art performance assessment methods.

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.

Recipes for diffuse correlation spectroscopy instrument design using commonly utilized hardware based on targets for signal-to-noise ratio and precision.

Over the recent years, a typical implementation of diffuse correlation spectroscopy (DCS) instrumentation has been adapted widely. However, there are no detailed and accepted recipes for designing such instrumentation to meet pre-defined signal-to-noise ratio (SNR) and precision targets. These require specific attention due to the subtleties of the DCS signals. Here, DCS experiments have been performed using liquid tissue simulating phantoms to study the effect of the detected photon count-rate, the number of parallel detection channels and the measurement duration on the precision and SNR to suggest scaling relations to be utilized for device design.

The LUCA device: a multi-modal platform combining diffuse optics and ultrasound imaging for thyroid cancer screening.

We present the LUCA device, a multi-modal platform combining eight-wavelength near infrared time resolved spectroscopy, sixteen-channel diffuse correlation spectroscopy and a clinical ultrasound in a single device. By simultaneously measuring the tissue hemodynamics and performing ultrasound imaging, this platform aims to tackle the low specificity and sensitivity of the current thyroid cancer diagnosis techniques, improving the screening of thyroid nodules. Here, we show a detailed description of the device, components and modules. Furthermore, we show the device tests performed through well established protocols for phantom validation, and the performance assessment for in vivo. The characterization tests demonstrate that LUCA device is capable of performing high quality measurements, with a precision in determining in vivo tissue optical and dynamic properties of better than 3%, and a reproducibility of better than 10% after ultrasound-guided probe repositioning, even with low photon count-rates, making it suitable for a wide variety of clinical applications.

Performance of measurands in time-domain optical brain imaging: depth selectivity versus contrast-to-noise ratio.

Time-domain optical brain imaging techniques introduce a number of different measurands for analyzing absorption changes located deep in the tissue, complicated by superficial absorption changes and noise. We implement a method that allows analysis, quantitative comparison and performance ranking of measurands under various conditions - including different values of reduced scattering coefficient, thickness of the superficial layer, and source-detector separation. Liquid phantom measurements and Monte Carlo simulations were carried out in two-layered geometry to acquire distributions of times of flight of photons and to calculate the total photon count, mean time of flight, variance, photon counts in time windows and ratios of photon counts in different time windows. Quantitative comparison of performance was based on objective metrics: relative contrast, contrast-to-noise ratio (CNR) and depth selectivity. Moreover, the product of CNR and depth selectivity was used to rank the overall performance and to determine the optimal source-detector separation for each measurand. Variance ranks the highest under all considered conditions.

Assessment of the brain ischemia during orthostatic stress and lower body negative pressure in air force pilots by near-infrared spectroscopy.

A methodology for the assessment of the cerebral hemodynamic reaction to normotensive hypovolemia, reduction in cerebral perfusion and orthostatic stress leading to ischemic hypoxia and reduced muscular tension is presented. Most frequently, the pilots of highly maneuverable aircraft are exposed to these phenomena. Studies were carried out using the system consisting of a chamber that generates low pressure around the lower part of the body - LBNP (lower body negative pressure) placed on the tilt table. An in-house developed 6-channel NIRS system operating at 735 and 850 nm was used in order to assess the oxygenation of the cerebral cortex, based on measurements of diffusely reflected light in reflectance geometry. The measurements were carried out on a group of 12 active pilots and cadets of the Polish Air Force Academy and 12 healthy volunteers. The dynamics of changes in cerebral oxygenation was evaluated as a response to LBNP stimuli with a simultaneous rapid change of the tilt table angle. Parameters based on calculated changes of total hemoglobin concentration were proposed allowing to evaluate differences in reactions observed in control subjects and pilots/cadets. The results of orthogonal partial least squares-discriminant analysis based on these parameters show that the subjects can be classified into their groups with 100% accuracy.

Influence of contrast-reversing frequency on the amplitude and spatial distribution of visual cortex hemodynamic responses.

Visual stimulation is one of the most commonly used paradigms for cerebral cortex function investigation. Experiments typically involve presenting to a volunteer a black-and-white checkerboard with contrast-reversing at a frequency of 4 to 16 Hz. The aim of the present study was to investigate the influence of the flickering frequency on the amplitude of changes in the concentration of oxygenated and deoxygenated hemoglobin. The hemoglobin concentrations were assessed with the use of a high resolution diffuse optical tomography method. Spatial distributions of changes in hemoglobin concentrations overlaying the visual cortex are shown for various stimuli frequencies. Moreover, the hemoglobin concentration changes obtained for different source-detector separations (from 1.5 to 5.4 cm) are presented. Our results demonstrate that the flickering frequency had a statistically significant effect on the induced oxyhemoglobin changes (p < 0,001). The amplitude of oxy hemoglobin concentration changes at a frequency of 8 Hz was higher in comparison with that measured at 4 Hz :[median(25th-75thpercentiles) 1.24 (0.94-1.71) vs. 0.92(0.73-1.28)µM, p < 0.001]; 12 Hz:[1.24 (0.94-1.71) vs. 1.04 (0.78-1.32) µM, p < 0.001]; and 16 Hz:[1.24 (0.94-1.71) vs. 1.15(0.87-1.48) µM, p < 0.001]. No significant differences were observed between the size of an area of activation for various frequencies. The demonstrated superiority of 8 Hz over other frequencies can advance understanding of visual stimulations and help guide future fNIRS protocols.

Depth-resolved assessment of changes in concentration of chromophores using time-resolved near-infrared spectroscopy: estimation of cytochrome-c-oxidase uncertainty by Monte Carlo simulations.

Time-resolved near-infrared spectroscopy (TR-NIRS) measurements can be used to recover changes in concentrations of tissue constituents ( Δ C ) by applying the moments method and the Beer-Lambert law. In this work we carried out the error propagation analysis allowing to calculate the standard deviations of uncertainty in estimation of the Δ C . Here, we show the process of choosing wavelengths for the evaluation of hemodynamic (oxy-, deoxyhemoglobin) and metabolic (cytochrome-c-oxidase (CCO)) responses within the brain tissue as measured with an in-house developed TR-NIRS multi-wavelength system, which measures at 16 consecutive wavelengths separated by 12.5 nm and placed between 650 and 950 nm. Data generated with Monte Carlo simulations on three-layered model (scalp, skull, brain) for wavelengths range from 650 to 950 nm were used to carry out the error propagation analysis for varying choices of wavelengths. For a detector with a spectrally uniform responsivity, the minimal standard deviation of the estimated changes in CCO within the brain layer, σ Δ C CCO brain = 0.40 µM, was observed for the 16 consecutive wavelengths from 725 to 912.5 nm. For realistic a detector model, i.e. the spectral responsivity characteristic is considered, the minimum, σ Δ C CCO brain = 0.47 µM, was observed at the 16 consecutive wavelengths from 688 to 875 nm. We introduce the method of applying the error propagation analysis to data as measured with spectral TR-NIRS systems to calculate uncertainty of recovery of tissue constituents concentrations.

Self-calibrating time-resolved near infrared spectroscopy.

Time-resolved near infrared spectroscopy is considered to be a gold standard technique when measuring absolute values of tissue optical properties, as it provides separable and independent information about both tissue absorption and scattering. However, time-resolved instruments require an accurate characterization by measuring the instrument response function in order to decouple the contribution of the instrument itself from the measurement. In this work, a new approach to the methodology of analysing time-resolved data is presented where the influence of instrument response function is eliminated from the data and a self-calibrating analysis is proposed. The proposed methodology requires an instrument to provide at least two wavelengths and allows spectral parameters recovery (optical properties or constituents concentrations and reduced scatter amplitude and power). Phantom and in-vivo data from two different time-resolved systems are used to validate the accuracy of the proposed self-calibrating approach, demonstrating that parameters recovery compared to the conventional curve fitting approach is within 10% and benefits from introducing a spectral constraint to the reconstruction problem. It is shown that a multi-wavelength time-resolved data can be used for parameters recovery directly without prior calibration (instrument response function measurement).

Confirmation of brain death using optical methods based on tracking of an optical contrast agent: assessment of diagnostic feasibility.

We aimed to determine whether optical methods based on bolus tracking of an optical contrast agent are useful for the confirmation of cerebral circulation cessation in patients being evaluated for brain death. Different stages of cerebral perfusion disturbance were compared in three groups of subjects: controls, patients with posttraumatic cerebral edema, and patients with brain death. We used a time-resolved near-infrared spectroscopy setup and indocyanine green (ICG) as an intravascular flow tracer. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was carried out to build statistical models allowing for group separation. Thirty of 37 subjects (81.1%) were classified correctly (8 of 9 control subjects, 88.9%; 13 of 15 patients with edema, 86.7%; and 9 of 13 patients with brain death, 69.2%; p < 0.0001). Depending on the combination of variables used in the OPLS-DA model, sensitivity, specificity, and accuracy were 66.7-92.9%, 81.8-92.9%, and 77.3-89.3%, respectively. The method was feasible and promising in the demanding intensive care unit environment. However, its accuracy did not reach the level required for brain death confirmation. The potential usefulness of the method may be improved by increasing the depth of light penetration, confirming its accuracy against other methods evaluating cerebral flow cessation, and developing absolute parameters for cerebral perfusion.

Time-resolved near infrared light propagation using frequency domain superposition.

Time-resolved temporal point spread function (TPSF) measurement of near infrared spectroscopic (NIRS) data allows the estimation of absorption and reduced scattering properties of biological tissues. Such analysis requires an iterative calculation of the theoretical TPSF curve using mathematical and computational models of the domain being imaged which are computationally complex and expensive. In this work, an efficient methodology for representing the TPSF data using a superposition of cosines calculated in frequency domain is presented. The proposed method is outlined and tested on finite element realistic models of the human neck and head. Using an adult head model containing ~140k nodes, the TPSF calculation at each node for one source is accelerated from 3.11 s to 1.29 s within an error limit of ± 5% related to the time domain calculation method.

Toward real-time diffuse optical tomography: accelerating light propagation modeling employing parallel computing on GPU and CPU.

Parameter recovery in diffuse optical tomography is a computationally expensive algorithm, especially when used for large and complex volumes, as in the case of human brain functional imaging. The modeling of light propagation, also known as the forward problem, is the computational bottleneck of the recovery algorithm, whereby the lack of a real-time solution is impeding practical and clinical applications. The objective of this work is the acceleration of the forward model, within a diffusion approximation-based finite-element modeling framework, employing parallelization to expedite the calculation of light propagation in realistic adult head models. The proposed methodology is applicable for modeling both continuous wave and frequency-domain systems with the results demonstrating a 10-fold speed increase when GPU architectures are available, while maintaining high accuracy. It is shown that, for a very high-resolution finite-element model of the adult human head with ∼600,000 nodes, consisting of heterogeneous layers, light propagation can be calculated at ∼0.25 s/excitation source.

Application of optical methods in the monitoring of traumatic brain injury: A review.

We present an overview of the wide range of potential applications of optical methods for monitoring traumatic brain injury. The MEDLINE database was electronically searched with the following search terms: "traumatic brain injury," "head injury," or "head trauma," and "optical methods," "NIRS," "near-infrared spectroscopy," "cerebral oxygenation," or "cerebral oximetry." Original reports concerning human subjects published from January 1980 to June 2015 in English were analyzed. Fifty-four studies met our inclusion criteria. Optical methods have been tested for detection of intracranial lesions, monitoring brain oxygenation, assessment of brain perfusion, and evaluation of cerebral autoregulation or intracellular metabolic processes in the brain. Some studies have also examined the applicability of optical methods during the recovery phase of traumatic brain injury . The limitations of currently available optical methods and promising directions of future development are described in this review. Considering the outstanding technical challenges, the limited number of patients studied, and the mixed results and opinions gathered from other reviews on this subject, we believe that optical methods must remain primarily research tools for the present. More studies are needed to gain confidence in the use of these techniques for neuromonitoring of traumatic brain injury patients.

Optimization of the method for assessment of brain perfusion in humans using contrast-enhanced reflectometry: multidistance time-resolved measurements.

The aim of the study was to determine optimal measurement conditions for assessment of brain perfusion with the use of optical contrast agent and time-resolved diffuse reflectometry in the near-infrared wavelength range. The source-detector separation at which the distribution of time of flights (DTOF) of photons provided useful information on the inflow of the contrast agent to the intracerebral brain tissue compartments was determined. Series of Monte Carlo simulations was performed in which the inflow and washout of the dye in extra- and intracerebral tissue compartments was modeled and the DTOFs were obtained at different source-detector separations. Furthermore, tests on diffuse phantoms were carried out using a time-resolved setup allowing the measurement of DTOFs at 16 source-detector separations. Finally, the setup was applied in experiments carried out on the heads of adult volunteers during intravenous injection of indocyanine green. Analysis of statistical moments of the measured DTOFs showed that the source-detector separation of 6 cm is recommended for monitoring of inflow of optical contrast to the intracerebral brain tissue compartments with the use of continuous wave reflectometry, whereas the separation of 4 cm is enough when the higher-order moments of DTOFs are available.

Prolonged postocclusive hyperemia response in patients with normal-tension glaucoma.

BACKGROUND: It is believed that endothelial dysfunction may be a link between systemic and ocular dysregulation in glaucoma. The aim of this study was to evaluate peripheral vascular reactive hyperemia in response to occlusion test and to correlate peripheral vascular findings with retrobulbar hemodynamics parameters in patients with normal-tension glaucoma. MATERIAL AND METHODS: Forty-eight patients with normal-tension glaucoma (mean age 58.1 years, 38 women) and 40 control subjects (mean age 54.1 years, 36 women) were subjected to a brachial arterial occlusion test and color Doppler imaging (LOGIQ 9, GE Medical Systems) of the retrobulbar arteries. Finger hyperemia was assessed by using a 2-channel laser Doppler flowmeter (MBF-3D, Moor Instruments, Ltd.). Time parameters (time to peak flow, half-time of hyperemia, time of recovery) and amplitude parameters (maximum hyperemia response, biological zero) of the post-occlusive reactive hyperemia signal pattern as well as velocities and resistance index of the ophthalmic, central retinal, and short posterior ciliary arteries were evaluated and compared between study groups. RESULTS: In glaucoma patients, time to peak flow and half-time of hyperemia were significantly longer (21.4 vs. 12.0 s, p=0.02 and 74.1 vs. 44.2 s, p=0.03, respectively) and biological zero was significantly lower (2.4 vs. 3.2, p=0.01) comparing with healthy subjects. In glaucoma patients, peak-systolic and end-diastolic velocities of central retinal artery were significantly lower (12.8 vs.14.1, p=0.03 and 3.9 vs. 4.7, p=0.01, respectively) and resistance index of this artery was significantly higher (0.69 vs. 0.67, p=0.03) compared to controls. In the glaucoma group, maximum hyperemic response was negatively correlated with the resistance index of temporal short posterior ciliary arteries (r=-0.4, p=0.01), whereas in the control group half-time of hyperemia was negatively correlated with end-diastolic velocity of the central retinal artery (r=-0.3, p=0.03). CONCLUSIONS: Arterial occlusion test elicited a prolonged systemic hyperemia response in patients with glaucoma as compared with healthy subjects. Retrobulbar blood flow alterations in glaucoma patients may be related to systemic vascular dysregulation.

Optical system based on time-gated, intensified charge-coupled device camera for brain imaging studies.

An imaging system for brain oxygenation based on a time-gated, intensified charge-coupled device camera was developed. It allows one to image diffusely reflected light from an investigated medium at defined time windows delayed with respect to the laser pulse. Applying a fast optomechanical switch to deliver the light at a wavelength of 780 nm to nine source fibers allowed one to acquire images in times as short as 4 s. Thus, the system can be applied in in vivo studies. The system was validated in phantom experiments, in which absorbing inclusions were localized at different depths and different lateral positions. Then, the decrease in absorption of the brain tissue related to increase in oxygenation was visualized in the motor cortex area during finger tapping by a healthy volunteer.

Estimation of speed distribution of particles moving in an optically turbid medium using decomposition of a laser-Doppler spectrum.

In this paper we present validation of laser-Doppler spectrum decomposition procedure in estimation of speed distribution of particles. Decomposition method is based on assumption that measured laser-Doppler spectrum can be approximated by linear combination of Doppler shift probability distributions calculated for different speeds of particles and anisotropy of light scattering in the medium. The Doppler shift probability distributions were calculated using Monte-Carlo simulations for Henyey-Greenstein scattering phase function. This decomposition method allows to obtain distribution of speeds of moving particles in the medium, not only average speed as it was possible in laser-Doppler perfusion monitors. Recently we reported that the method was positively verified on spectra generated for different speed distributions using Monte Carlo simulations. In this study we present results of application of the decomposition procedure in analysis of laser-Doppler spectra obtained in physical phantom experiments. A diluted solution of milk was pumped through a tube with different speeds. The dependence of the obtained distributions of speed of moving particles on the speed of flow was observed. Laser-Doppler spectra obtained during in-vivo experiment were also successfully decomposed. A healthy volunteer was investigated and the spectra of laser-Doppler signal during postocclusive hyperemia test were recorded and analyzed. We conclude that the spectrum decomposition procedure can be successfully applied in analysis of the measured laser-Doppler spectra and the amount of information provided by laser-Doppler technique can be significantly increased.