Detectability of hemodynamic oscillations in cerebral cortex through functional near-infrared spectroscopy: a simulation study.

Significance: We explore the feasibility of using time-domain (TD) and continuous-wave (CW) functional near-infrared spectroscopy (fNIRS) to monitor brain hemodynamic oscillations during resting-state activity in humans, a phenomenon that is of increasing interest in the scientific and medical community and appears to be crucial to advancing the understanding of both healthy and pathological brain functioning. Aim: Our general object is to maximize fNIRS sensitivity to brain resting-state oscillations. More specifically, we aim to define comprehensive guidelines for optimizing main operational parameters in fNIRS measurements [average photon count rate, measurement length, sampling frequency, and source-detector distance (SSD)]. In addition, we compare TD and CW fNIRS performance for the detection and localization of oscillations. Approach: A series of synthetic TD and CW fNIRS signals were generated by exploiting the solution of the diffusion equation for two different geometries of the probed medium: a homogeneous medium and a bilayer medium. Known and periodical perturbations of the concentrations of oxy- and deoxy-hemoglobin were imposed in the medium, determining changes in its optical properties. The homogeneous slab model was used to determine the effect of multiple measurement parameters on fNIRS sensitivity to oscillatory phenomena, and the bilayer model was used to evaluate and compare the abilities of TD and CW fNIRS in detecting and isolating oscillations occurring at different depths. For TD fNIRS, two approaches to enhance depth-selectivity were evaluated: first, a time-windowing of the photon distribution of time-of-flight was performed, and then, the time-dependent mean partial pathlength (TMPP) method was used to retrieve the hemoglobin concentrations in the medium. Results: In the homogeneous medium case, the sensitivity of TD and CW fNIRS to periodical perturbations of the optical properties increases proportionally with the average photon count rate, the measurement length, and the sampling frequency and approximatively with the square of the SSD. In the bilayer medium case, the time-windowing method can detect and correctly localize the presence of oscillatory components in the TD fNIRS signal, even in the presence of very low photon count rates. The TMPP method demonstrates how to correctly retrieve the periodical variation of hemoglobin at different depths from the TD fNIRS signal acquired at a single SSD. For CW fNIRS, measurements taken at typical SSDs used for short-separation channel regression show notable sensitivity to oscillations occurring in the deep layer, challenging the assumptions underlying this correction method when the focus is on analyzing oscillatory phenomena. Conclusions: We demonstrated that the TD fNIRS technique allows for the detection and depth-localization of periodical fluctuations of the hemoglobin concentrations within the probed medium using an acquisition at a single SSD, offering an alternative to multi-distance CW fNIRS setups. Moreover, we offered some valuable guidelines that can assist researchers in defining optimal experimental protocols for fNIRS studies.

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

[This corrects the article on p. 5994 in vol. 14, PMID: 38021143.].

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.

Statistics of maximum photon penetration depth in a two-layer diffusive medium.

We present numerical results for the probability density function f(z) and for the mean value of photon maximum penetration depth zmax> in a two-layer diffusive medium. Both time domain and continuous wave regime are considered with several combinations of the optical properties (absorption coefficient, reduced scattering coefficient) of the two layers, and with different geometrical configurations (source detector distance, thickness of the upper layer). Practical considerations on the design of time domain and continuous wave systems are derived. The methods and the results are of interest for many research fields such as biomedical optics and advanced microscopy.

Application limits of the scaling relations for Monte Carlo simulations in diffuse optics. Part 1: theory.

Monte Carlo (MC) is a powerful tool to study photon migration in scattering media, yet quite time-consuming to solve inverse problems. To speed up MC-simulations, scaling relations can be applied to an existing initial MC-simulation to generate a new data-set with different optical properties. We named this approach trajectory-based since it uses the knowledge of the detected photon trajectories of the initial MC-simulation, in opposition to the slower photon-based approach, where a novel MC-simulation is rerun with new optical properties. We investigated the convergence and applicability limits of the scaling relations, both related to the likelihood that the sample of trajectories considered is representative also for the new optical properties. For absorption, the scaling relation contains smoothly converging Lambert-Beer factors, whereas for scattering it is the product of two quickly diverging factors, whose ratio, for NIRS cases, can easily reach ten orders of magnitude. We investigated such instability by studying the probability-distribution for the number of scattering events in trajectories of given length. We propose a convergence test of the scattering scaling relation based on the minimum-maximum number of scattering events in recorded trajectories. We also studied the dependence of MC-simulations on optical properties, most critical in inverse problems, finding that scattering derivatives are ascribed to small deviations in the distribution of scattering events from a Poisson distribution. This paper, which can also serve as a tutorial, helps to understand the physics of the scaling relations with the causes of their limitations and devise new strategies to deal with them.

Quality Characteristics, Sensory Profiles and Ethylene Production of Stored 'Abate Fetel' Pears Sorted at Harvest by Time-Resolved Reflectance Spectroscopy.

Time-resolved reflectance spectroscopy (TRS), a nondestructive technique, can help the industry to provide high-quality fruit to encourage pear consumption. The absorption coefficient measured by TRS at 670 nm (µa670) represents a maturity index for pear fruit, with less mature pears high µa670 and more mature low µa670. The aim of this work was to study the quality characteristics, the sensory profiles and the ethylene production of 'Abate Fetel' pears sorted at harvest in different TRS maturity classes and stored in different atmospheres. At harvest, 540 pears were measured by TRS for µa670, ranked by µa670 in three maturity classes (less-LeM, medium-MeM and more-MoM mature) and randomized in nine samples according to 1-MCP treatment (treated, control), storage time (4-6 months) and atmosphere (air-NA; CA: 8-12 kPa O2, 1 kPa CO2). Fruits were examined at harvest and after 7 days of poststorage shelf life for skin color, firmness, soluble solids, acidity and ethylene production and were submitted to sensory analysis. At harvest and after storage, MoM pears were less green and showed a higher SSC content than LeM ones. After storage, MoM pears produced less ethylene and were perceived to be firmer (especially in 1-MCP-treated pears), more astringent and less juicy (when stored for 6 months) than LeM ones.

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.

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.

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.

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.

Reproducibility of identical solid phantoms.

SIGNIFICANCE: Tissue-like solid phantoms with identical optical properties, known within tolerant uncertainty, are of crucial importance in diffuse optics for instrumentation assessment, interlaboratory comparison studies, industrial standards, and multicentric clinical trials. AIM: The reproducibility in fabrication of homogeneous solid phantoms is focused based on spectra measurements by instrument comparisons grounded on the time-resolved diffuse optics. APPROACH: Epoxy-resin and silicone phantoms are considered as matrices and both employ three different instruments for time-resolved diffuse spectroscopy within the spectral range of 540 to 1100 nm. In particular, we fabricated two batches of five phantoms each in epoxy resin and silicone. Then, we evaluated the intra- and interbatch variability with respect to the instrument precision, by considering the coefficient of variation (CV) of absorption and reduced scattering coefficients. RESULTS: We observed a similar precision for the three instruments, within 2% for repeated measurements on the same phantom. For epoxy-resin phantoms, the intra- and the interbatch variability reached the instrument precision limit, demonstrating a very good phantom reproducibility. For the silicone phantoms, we observed larger values for intra- and interbatch variability. In particular, at worst, for reduced scattering coefficient interbatch CV was about 5%. CONCLUSIONS: Results suggest that the fabrication of solid phantoms, especially considering epoxy-resin matrix, is highly reproducible, even if they come from different batch fabrications and are measured using different instruments.

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.

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.