Non-Invasive Monitoring of Microvascular Oxygenation and Reactive Hyperemia using Hybrid, Near-Infrared Diffuse Optical Spectroscopy for Critical Care.

The detection of levels of impairment in microvascular oxygen consumption and reactive hyperemia is vital in critical care. However, there are no practical means for a robust and quantitative evaluation. This paper describes a protocol to evaluate these impairments using a hybrid near-infrared diffuse optical device. The device contains modules for near-infrared time-resolved and diffuse correlation spectroscopies and pulse-oximetry. These modules allow the non-invasive, continuous, and real-time measurement of the absolute, microvascular blood/tissue oxygen saturation (StO2) and the blood flow index (BFI) along with the peripheral arterial oxygen saturation (SpO2). This device uses an integrated, computer-controlled tourniquet system to execute a standardized protocol with optical data acquisition from the brachioradialis muscle. The standardized vascular occlusion test (VOT) takes care of the variations in the occlusion duration and pressure reported in the literature, while the automation minimizes inter-operator differences. The protocol we describe focuses on a 3-min occlusion period but the details described in this paper can readily be adapted to other durations and cuff pressures, as well as other muscles. The inclusion of an extended baseline and post-occlusion recovery period measurement allows the quantification of the baseline values for all the parameters and the blood/tissue deoxygenation rate that corresponds to the metabolic rate of oxygen consumption. Once the cuff is released, we characterize the tissue reoxygenation rate, magnitude, and duration of the hyperemic response in BFI and StO2. These latter parameters correspond to the quantification of the reactive hyperemia, which provides information about the endothelial function. Furthermore, the above-mentioned measurements of the absolute concentration of oxygenated and deoxygenated hemoglobin, BFI, the derived metabolic rate of oxygen consumption, StO2, and SpO2 provide a yet-to-be-explored rich data set that can exhibit disease severity, personalized therapeutics, and management interventions.

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.

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.

Non-invasive estimation of in vivo optical properties and hemodynamic parameters of domestic animals: a preliminary study on horses, dogs, and sheep.

Biosensors applied in veterinary medicine serve as a noninvasive method to determine the health status of animals and, indirectly, their level of welfare. Near infrared spectroscopy (NIRS) has been suggested as a technology with this application. This study presents preliminary in vivo time domain NIRS measurements of optical properties (absorption coefficient, reduced scattering coefficient, and differential pathlength factor) and hemodynamic parameters (concentration of oxygenated hemoglobin, deoxygenated hemoglobin, total hemoglobin, and tissue oxygen saturation) of tissue domestic animals, specifically of skeletal muscle (4 dogs and 6 horses) and head (4 dogs and 19 sheep). The results suggest that TD NIRS in vivo measurements on domestic animals are feasible, and reveal significant variations in the optical and hemodynamic properties among tissue types and species. In horses the different optical and hemodynamic properties of the measured muscles can be attributed to the presence of a thicker adipose layer over the muscle in the Longissimus Dorsi and in the Gluteus Superficialis as compared to the Triceps Brachii. In dogs the absorption coefficient is higher in the head (temporalis musculature) than in skeletal muscles. The smaller absorption coefficient for the head of the sheep as compared to the head of dogs may suggest that in sheep we are indeed reaching the brain cortex while in dog light penetration can be hindered by the strongly absorbing muscle covering the cranium.

Cerebrovascular reactivity to carbon dioxide tension in newborns: data from combined time-resolved near-infrared spectroscopy and diffuse correlation spectroscopy.

Significance: Critically ill newborns are at risk of brain damage from cerebrovascular disturbances. A cerebral hemodynamic monitoring system would have the potential role to guide targeted intervention. Aim: To obtain, in a population of newborn infants, simultaneous near-infrared spectroscopy (NIRS)-based estimates of cerebral tissue oxygen saturation (StO2) and blood flow during variations of carbon dioxide tension (pCO2) levels within physiologic values up to moderate permissive hypercapnia, and to examine if the derived estimate of metabolic rate of oxygen would stay constant, during the same variations. Approach: We enrolled clinically stable mechanically ventilated newborns at postnatal age >24 h without brain abnormalities at ultrasound. StO2 and blood flow index were measured using a non-invasive device (BabyLux), which combine time-resolved NIRS and diffuse-correlation spectroscopy. The effect of changes in transcutaneous pCO2 on StO2, cerebral blood flow (CBF), and cerebral metabolic rate of oxygen index (tCMRO2i) were estimated. Results: Ten babies were enrolled and three were excluded. Median GA at enrollment was 39 weeks and median weight 2720 g. StO2 increased 0.58% (95% CI 0.55; 0.61, p<0.001), CBF 2% (1.9; 2.3, p<0.001), and tCMRO2 0.3% (0.05; 0.46, p=0.017) per mmHg increase in pCO2. Conclusions: BabyLux device detected pCO2-induced changes in cerebral StO2 and CBF, as expected. The small statistically significant positive relationship between pCO2 and tCMRO2i variation is not considered clinically relevant and we are inclined to consider it as an artifact.

Motor cortex hemodynamic response to goal-oriented and non-goal-oriented tasks in healthy subjects.

Background: Motor disorders are one of the world's major scourges, and neuromotor rehabilitation is paramount for prevention and monitoring plans. In this scenario, exercises and motor tasks to be performed by patients are crucial to follow and assess treatments' progression and efficacy. Nowadays, in clinical environments, quantitative assessment of motor cortex activities during task execution is rare, due to the bulkiness of instrumentation and the need for immobility during measurements [e.g., functional magnetic resonance imaging (MRI)]. Functional near-infrared spectroscopy (fNIRS) can contribute to a better understanding of how neuromotor processes work by measuring motor cortex activity non-invasively in freely moving subjects. Aim: Exploit fNIRS to measure functional activation of the motor cortex area during arm-raising actions. Design: All subjects performed three different upper limbs motor tasks: arm raising (non-goal-oriented), arm raising and grasping (goal oriented), and assisted arm raising (passive task). Each task was repeated ten times. The block design for each task was divided into 5 seconds of baseline, 5 seconds of activity, and 15 seconds of recovery. Population: Sixteen healthy subjects (11 males and 5 females) with an average (+/- standard deviation) of 37.9 (+/- 13.0) years old. Methods: Cerebral hemodynamic responses have been recorded in two locations, motor cortex (activation area) and prefrontal cortex (control location) exploiting commercial time-domain fNIRS devices. Haemodynamic signals were analyzed, separating the brain cortex hemodynamic response from extracerebral hemodynamic variations. Results: The hemodynamic response was recorded in the cortical motor area for goal-oriented and not-goaloriented tasks, while no response was noticed in the control location (prefrontal cortex position). Conclusions: This study provides a basis for canonical upper limb motor cortex activations that can be potentially compared to pathological cerebral responses in patients. It also highlights the potential use of TD-fNIRS to study goal-oriented versus non-goaloriented motor tasks. Impact: the findings of this study may have implications for clinical rehabilitation by providing a better understanding of the neural mechanisms underlying goal-oriented versus non-goal-oriented motor tasks. This may lead to more effective rehabilitation strategies for individuals with motor disorders and a more effective diagnosis of motor dysfunction supported by objective and quantitative neurophysiological readings.

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.

Robustness of tissue oxygenation estimates by continuous wave space-resolved near infrared spectroscopy.

Significance: Continuous wave near infrared spectroscopy (CW-NIRS) is widely exploited in clinics to estimate skeletal muscles and brain cortex oxygenation. Spatially resolved spectroscopy (SRS) is generally implemented in commercial devices. However, SRS suffers from two main limitations: the a priori assumption on the spectral dependence of the reduced scattering coefficient [µs'(λ)] and the modeling of tissue as homogeneous. Aim: We studied the accuracy and robustness of SRS NIRS. We investigated the errors in retrieving hemodynamic parameters, in particular tissue oxygen saturation (StO2), when µs'(λ) was varied from expected values, and when layered tissue was considered. Approach: We simulated hemodynamic variations mimicking real-life scenarios for skeletal muscles. Simulations were performed by exploiting the analytical solutions of the photon diffusion equation in different geometries: (1) semi-infinite homogeneous medium and constant µs'(λ); (2) semi-infinite homogeneous medium and linear changes in µs'(λ); (3) two-layered media with a superficial thickness s1=5, 7.5, 10 mm and constant µs'(λ). All simulated data were obtained at source-detector distances ρ=35, 40, 45 mm, and analyzed with the SRS approach to derive hemodynamic parameters (concentration of oxygenated and deoxygenated hemoglobin, total hemoglobin concentration, and tissue oxygen saturation, StO2) and their relative error. Results: Variations in µs'(λ) affect the estimated StO2 (up to ±10%), especially if changes are different at the two wavelengths. However, the main limitation of the SRS method is the presence of a superficial layer: errors strongly larger than 20% were retrieved for the estimated StO2 when the superficial thickness exceeds 5 mm. Conclusions: These results highlight the need for more sophisticated strategies (e.g., the use of multiple short and long distances) to reduce the influence of superficial tissues in retrieving hemodynamic parameters and warn the SRS users to be aware of the intrinsic limitation of this approach, particularly when exploited in the clinical environment.

Multi-laboratory performance assessment of diffuse optics instruments: the BitMap exercise.

SIGNIFICANCE: Multi-laboratory initiatives are essential in performance assessment and standardization-crucial for bringing biophotonics to mature clinical use-to establish protocols and develop reference tissue phantoms that all will allow universal instrument comparison. AIM: The largest multi-laboratory comparison of performance assessment in near-infrared diffuse optics is presented, involving 28 instruments and 12 institutions on a total of eight experiments based on three consolidated protocols (BIP, MEDPHOT, and NEUROPT) as implemented on three kits of tissue phantoms. A total of 20 synthetic indicators were extracted from the dataset, some of them defined here anew. APPROACH: The exercise stems from the Innovative Training Network BitMap funded by the European Commission and expanded to include other European laboratories. A large variety of diffuse optics instruments were considered, based on different approaches (time domain/frequency domain/continuous wave), at various stages of maturity and designed for different applications (e.g., oximetry, spectroscopy, and imaging). RESULTS: This study highlights a substantial difference in hardware performances (e.g., nine decades in responsivity, four decades in dark count rate, and one decade in temporal resolution). Agreement in the estimates of homogeneous optical properties was within 12% of the median value for half of the systems, with a temporal stability of <5 % over 1 h, and day-to-day reproducibility of <3 % . Other tests encompassed linearity, crosstalk, uncertainty, and detection of optical inhomogeneities. CONCLUSIONS: This extensive multi-laboratory exercise provides a detailed assessment of near-infrared Diffuse optical instruments and can be used for reference grading. The dataset-available soon in an open data repository-can be evaluated in multiple ways, for instance, to compare different analysis tools or study the impact of hardware implementations.

Effects and correctability of pile-up distortion using established figures of merit in time-domain diffuse optics at extreme photon rates.

Time-domain diffuse optics (TD-DO) allows one to probe diffusive media with recognized advantages over other working domains but suffers from a poor signal-to-noise ratio (SNR) resulting from the need to build-up the histogram of single-photon arrival times with maximum count rates (CR) of few percent of the laser pulse rate to avoid the so-called "pile-up" distortion. Here we explore the feasibility of TD-DO under severe pile-up conditions with a systematic in-silico/experimental study evaluating the effects and correctability of the distortion by means of shared figures of merit. In-silico, we demonstrate that pile-up correction allows one the retrieval of homogeneous optical properties with average error < 1% up to a CR > 99%, while the optimal CR needed to detect localized perturbation was found to be 83%. Experiments reported here confirm these findings despite exhibiting higher accuracy errors in the retrieval of homogeneous optical properties and higher noise in the detection of localized absorption perturbations, but in line with the state-of-the-art systems. This work validates a new working regime for TD-DO, demonstrating an increase of the SNR at constant acquisition time, but also potentially leading in the future to previously unrealizable measurements of dynamic phenomena or in spatial scanning applications.

Reliable Fast (20 Hz) Acquisition Rate by a TD fNIRS Device: Brain Resting-State Oscillation Studies.

A high power setup for multichannel time-domain (TD) functional near infrared spectroscopy (fNIRS) measurements with high efficiency detection system was developed. It was fully characterized based on international performance assessment protocols for diffuse optics instruments, showing an improvement of the signal-to-noise ratio (SNR) with respect to previous analogue devices, and allowing acquisition of signals with sampling rate up to 20 Hz and source-detector distance up to 5 cm. A resting-state measurement on the motor cortex of a healthy volunteer was performed with an acquisition rate of 20 Hz at a 4 cm source-detector distance. The power spectrum for the cortical oxy- and deoxyhemoglobin is also provided.

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.

Optical characterization of 3D printed PLA and ABS filaments for diffuse optics applications.

The interest for Fused Deposition Modelling (FDM) in the field of Diffuse Optics (DO) is rapidly increasing. The most widespread FDM materials are polylactic acid (PLA) and acrylonitrile butadiene styrene (ABS), thanks to their low cost and easiness-to-print. This is why, in this study, 3D printed samples of PLA and ABS materials were optically characterized in the range from the UV up to the IR wavelengths, in order to test their possible employment for probe construction in DO applications. To this purpose, measurements with Near Infrared Spectroscopy and Diffuse Correlation Spectroscopy techniques were considered. The results obtained show how the material employed for probe construction can negatively affect the quality of DO measurements.

Accuracy of homogeneous models for photon diffusion in estimating neonatal cerebral hemodynamics by TD-NIRS.

We assessed the accuracy of homogenous (semi-infinite, spherical) photon diffusion models in estimating absolute hemodynamic parameters of the neonatal brain in realistic scenarios (ischemia, hyperoxygenation, and hypoventilation) from 1.5 cm interfiber distance TD NIRS measurements. Time-point-spread-functions in 29- and 44-weeks postmenstrual age head meshes were simulated by the Monte Carlo method, convoluted with a real instrument response function, and then fitted with photon diffusion models. The results show good accuracy in retrieving brain oxygen saturation, and severe underestimation of total cerebral hemoglobin, suggesting the need for more complex models of analysis or of larger interfiber distances to precisely monitor all hemodynamic parameters.

Time resolved speckle contrast optical spectroscopy at quasi-null source-detector separation for non-invasive measurement of microvascular blood flow.

Time (or path length) resolved speckle contrast optical spectroscopy (TD-SCOS) at quasi-null (2.85 mm) source-detector separation was developed and demonstrated. The method was illustrated by in vivo studies on the forearm muscle of an adult subject. The results have shown that selecting longer photon path lengths results in higher hyperemic blood flow change and a faster return to baseline by a factor of two after arterial cuff occlusion when compared to SCOS without time resolution. This indicates higher sensitivity to the deeper muscle tissue. In the long run, this approach may allow the use of simpler and cheaper detector arrays compared to time resolved diffuse correlation spectroscopy that are based on readily available technologies. Hence, TD-SCOS may increase the performance and decrease cost of devices for continuous non-invasive, deep tissue blood flow monitoring.

Effect of adipose tissue thickness and tissue optical properties on the differential pathlength factor estimation for NIRS studies on human skeletal muscle.

We propose a quantitative and systematic investigation of the differential pathlength factor (DPF) behavior for skeletal muscles and its dependence on different factors, such as the subcutaneous adipose tissue thickness (ATT), the variations of the tissue absorption (µa ) and reduced scattering (µ's ) coefficients, and the source-detector distance. A time domain (TD) NIRS simulation study is performed in a two-layer geometry mimicking a human skeletal muscle with an overlying adipose tissue layer. The DPF decreases when µa increases, while it increases when µ's increases. Moreover, a positive correlation between DPF and ATT is found. These results are supported by an in-vivo TD NIRS study on vastus lateralis and biceps brachii muscles of eleven subjects at rest, showing a high inter-subject and inter-muscle variability.

Monitoring the motor cortex hemodynamic response function in freely moving walking subjects: a time-domain fNIRS pilot study.

Significance: This study is a preliminary step toward the identification of a noninvasive and reliable tool for monitoring the presence and progress of gaiting dysfunctions. Aim: We present the results of a pilot study for monitoring the motor cortex hemodynamic response function (HRF) in freely walking subjects, with time-domain functional near-infrared spectroscopy (TD fNIRS). Approach: A compact and wearable single-channel TD fNIRS oximeter was employed. The lower limb motor cortex area of three healthy subjects was monitored while performing two different freely moving gaiting tasks: forward and backward walking. Results: The time course of oxygenated and deoxygenated hemoglobin was measured during the different walking tasks. Brain motor cortex hemodynamic activations have been analyzed throughout an adaptive HRF fitting procedure, showing a greater involvement of motor area in the backward walking task. By comparison with the HRF obtained in a finger-tapping task performed in a still condition, we excluded any effect of motion artifacts in the gaiting tasks. Conclusions: For the first time to our knowledge, the hemodynamic motor cortex response was measured by TD fNIRS during natural, freely walking exercises. The cortical response during forward and backward walking shows differences, possibly related to the diverse involvement of the motor cortex in the two types of gaiting.