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Bilateral cochlear implant (BiCI) usage makes binaural benefits a possibility for implant users. Yet for BiCI users, limited access to interaural time difference (ITD) cues and reduced saliency of interaural level difference (ILD) cues restricts perceptual benefits of spatially separating a target from masker sounds. The present study explored whether magnifying ILD cues improves intelligibility of masked speech for BiCI listeners in a "symmetrical-masker" configuration, which ensures that neither ear benefits from a long-term positive target-to-masker ratio (TMR) due to naturally occurring ILD cues. ILD magnification estimates moment-to-moment ITDs in octave-wide frequency bands, and applies corresponding ILDs to the target-masker mixtures reaching the two ears at each specific time and frequency band. ILD magnification significantly improved intelligibility in two experiments: one with NH listeners using vocoded stimuli and one with BiCI users. BiCI listeners showed no benefit of spatial separation between target and maskers with natural ILDs, even for the largest target-masker separation. Because ILD magnification relies on and manipulates only the mixed signals at each ear, the strategy never alters the monaural TMR in either ear at any time. Thus, the observed improvements to masked speech intelligibility come from binaural effects, likely from increased perceptual separation of the competing sources., Competing Interests: VI.CONFLICTS OF INTEREST The authors have no conflicts to disclose.

Although existing literature covers significant detail on the physiology of human freediving, the lack of standardized protocols has hindered comparisons due to confounding variables such as exercise and depth. By accounting for these variables, direct depth-dependent impacts on cardiovascular and blood oxygen regulation can be investigated. In this study, depth-dependent effects on 1 ) cerebral hemodynamic and oxygenation changes, 2 ) arterial oxygen saturation ([Formula: see text]), and 3 ) heart rate during breath-hold diving without confounding effects of exercise were investigated. Six freedivers (51.0 ± 12.6 yr; means ± SD), instrumented with continuous-wave near-infrared spectroscopy for monitoring cerebral hemodynamic and oxygenation measurements, heart rate, and [Formula: see text], performed sled-assisted breath-hold dives to 15 m and 42 m. Arterial blood gas tensions were validated through cross-sectional periodic blood sampling. Cerebral hemodynamic changes were characteristic of breath-hold diving, with changes during ascent from both depths likely driven by decreasing [Formula: see text] due to lung expansion. Although [Formula: see text] was significantly lower following 42-m dives [ t (5) = -4.183, P < 0.05], mean cerebral arterial-venous blood oxygen saturation remained at 74% following dives to both depths. Cerebral oxygenation during ascent from 42 m may have been maintained through increased arterial delivery. Heart rate was variable with no significant difference in minimum heart rate between both depths [ t (5) = -1.017, P > 0.05]. This study presents a standardized methodology, which could provide a basis for future research on human freediving physiology and uncover ways in which freedivers can reduce potential risks of the sport. NEW & NOTEWORTHY We present a standardized methodology in which trained breath-hold divers instrumented with wearable near-infrared spectroscopy (NIRS) technology and a cannula for arterial blood sampling completed sled-assisted dives to two different dive depths to account for the confounding factors of exercise and depth during breath-hold diving. In our investigation, we highlight the utility of wearable NIRS systems for continuous hemodynamic and oxygenation monitoring to investigate the impacts of hydrostatic pressure on cardiovascular and blood oxygen regulation.

Significance: Near-infrared optical imaging methods have shown promise for monitoring response to neoadjuvant chemotherapy (NAC) for breast cancer, with endogenous contrast coming from oxy- and deoxyhemoglobin. Spatial frequency domain imaging (SFDI) could be used to detect this contrast in a low-cost and portable format, but it has limited imaging depth. It is possible that local tissue compression could be used to reduce the effective tumor depth., Aim: To evaluate the potential of SFDI for therapy response prediction, we aim to predict how changes to tumor size, stiffness, and hemoglobin concentration would be reflected in contrast measured by SFDI under tissue compression., Approach: Finite element analysis of compression on an inclusion-containing soft material is combined with Monte Carlo simulation to predict the measured optical contrast., Results: When the effect of compression on blood volume is not considered, contrast gain from compression increases with the size and stiffness of the inclusion and decreases with the inclusion depth. With a model of reduction of blood volume from compression, compression reduces imaging contrast, an effect that is greater for larger inclusions and stiffer inclusions at shallower depths., Conclusions: This computational modeling study represents a first step toward tracking tumor changes induced by NAC using SFDI and local compression., (© 2024 The Authors.)

Transabdominal fetal pulse oximetry offers a promising approach to improve fetal monitoring and reduce unnecessary interventions. Utilizing realistic 3D geometries derived from MRI scans of pregnant women, we conducted photon simulations to determine optimal source-detector configurations for detecting fetal heart rate and oxygenation. Our findings demonstrate the theoretical feasibility of measuring fetal signals at depths up to 30 mm using source-detector (SD) distances greater than 100 mm and wavelengths between 730 and 850 nm. Furthermore, we highlight the importance of customizing SD configurations based on fetal position and maternal anatomy. These insights pave the way for enhanced non-invasive fetal monitoring in clinical application., Competing Interests: JMK and MPD have conflict of interest with Raydiant Oximetry, Inc., (© 2024 The Author(s).)

Diffuse optical tomography (DOT) enhances the localization accuracy of neural activity measured with electroencephalography (EEG) while preserving EEG's high temporal resolution. However, the spatial resolution of reconstructed activity diminishes for deeper neural sources. In this study, we analyzed DOT-enhanced EEG localization of neural sources modeled at depths ranging from 11-25 mm in simulations. Our findings reveal systematic biases in reconstructed depth related to DOT channel length. To address this, we developed a data-informed method for selecting DOT channels to improve the spatial accuracy of DOT-enhanced EEG reconstruction. Using our method, the average absolute reconstruction depth errors of DOT reconstruction across all depths are 0.9 ± 0.6 mm, 1.2 ± 0.9 mm, and 1.2 ± 1.1 mm under noiseless, low-level noise, and high-level noise conditions, respectively. In comparison, using fixed channel lengths resulted in errors of 2.6 ± 1.5 mm, 5.0 ± 2.6 mm, and 7.3 ± 4.5 mm under the same conditions. Consequently, our method improved the depth accuracy of DOT reconstructions and facilitated the use of more accurate spatial priors for EEG reconstructions, enhancing the overall precision of the technique., Competing Interests: No conflict of interest is declared., (© 2024 Optica Publishing Group.)

The editorial introduces the JBO Special Issue on Pulse Oximetry., (© 2025 The Authors.)

Significance: Near-infrared spectroscopy (NIRS) is a non-invasive optical method that measures changes in hemoglobin concentration and oxygenation. The measured light intensity is susceptible to reduced signal quality due to the presence of melanin., Aim: We quantify the influence of melanin concentration on NIRS measurements taken with a frequency-domain near-infrared spectroscopy system using 690 and 830 nm., Approach: Using a forehead NIRS probe, we measured 35 healthy participants and investigated the correlation between melanin concentration indices, which were determined using a colorimeter, and several key metrics from the NIRS signal. These metrics include signal-to-noise ratio (SNR), two measurements of oxygen saturation (arterial oxygen saturation, SpO 2 , and tissue oxygen saturation, StO 2 ), and optical properties represented by the absorption coefficient ( μ a ) and the reduced scattering coefficient ( μ s ' )., Results: We found a significant negative correlation between the melanin index and the SNR estimated in oxy-hemoglobin signals ( r s = - 0.489 , p = 0.006 ) and SpO 2 levels ( r s = - 0.413 , p = 0.023 ). However, no significant changes were observed in the optical properties and StO 2 ( r s = - 0.146 , p = 0.44 )., Conclusions: We found that estimated SNR and SpO 2 values show a significant decline and dependence on the melanin index, whereas StO 2 and optical properties do not show any correlation with the melanin index., (© 2024 The Authors.)

Significance: Diffuse correlation spectroscopy (DCS) is an optical method to measure relative changes in cerebral blood flow (rCBF) in the microvasculature. Each heartbeat generates a pulsatile signal with distinct morphological features that we hypothesized to be related to intracranial compliance (ICC)., Aim: We aim to study how three features of the pulsatile rCBF waveforms: the augmentation index (AIx), the pulsatility index, and the area under the curve, change with respect to ICC. We describe ICC as a combination of vascular compliance and extravascular compliance., Approach: Since patients with Chiari malformations (CM) ( n = 30 ) have been shown to have altered extravascular compliance, we compare the morphology of rCBF waveforms in CM patients with age-matched healthy control ( n = 30 )., Results: AIx measured in the supine position was significantly less in patients with CM compared to healthy controls ( p < 0.05 ). Since physiologic aging also leads to changes in vessel stiffness and intravascular compliance, we evaluate how the rCBF waveform changes with respect to age and find that the AIx feature was strongly correlated with age ( R healthy subjects = - 0.63 , R preoperative   CM   patient = - 0.70 , and R postoperative   CM   patients = - 0.62 , p < 0.01 )., Conclusions: These results suggest that the AIx measured in the cerebral microvasculature using DCS may be correlated to changes in ICC., (© 2024 The Authors.)

Significance: Pulse oximetry estimates the arterial oxygen saturation of hemoglobin ( SaO 2 ) based on relative changes in light intensity at the cardiac frequency. Commercial pulse oximeters require empirical calibration on healthy volunteers, resulting in limited accuracy at low oxygen levels. An accurate, self-calibrated method for estimating SaO 2 is needed to improve patient monitoring and diagnosis., Aim: Given the challenges of calibration at low SaO 2 levels, we pursued the creation of a self-calibrated algorithm that can effectively estimate SaO 2 across its full range. Our primary objective was to design and validate our calibration-free method using data collected from human subjects., Approach: We developed an algorithm based on diffuse optical spectroscopy measurements of cardiac pulses and the modified Beer-Lambert law (mBLL). Recognizing that the photon mean pathlength ( ⟨ L ⟩ ) varies with SaO 2 related absorption changes, our algorithm aligns/fits the normalized ⟨ L ⟩ (across wavelengths) obtained from optical measurements with its analytical representation. We tested the algorithm with human freedivers performing breath-hold dives. A continuous-wave near-infrared spectroscopy probe was attached to their foreheads, and an arterial cannula was inserted in the radial artery to collect arterial blood samples at different stages of the dive. These samples provided ground-truth SaO 2 via a blood gas analyzer, enabling us to evaluate the accuracy of SaO 2 estimation derived from the NIRS measurement using our self-calibrated algorithm., Results: The self-calibrated algorithm significantly outperformed the conventional method (mBLL with a constant ⟨ L ⟩ ratio) for SaO 2 estimation through the diving period. Analyzing 23 ground-truth SaO 2 data points ranging from 41% to 100%, the average absolute difference between the estimated SaO 2 and the ground truth SaO 2 is 4.23 % ± 5.16 % for our algorithm, significantly lower than the 11.25 % ± 13.74 % observed with the conventional approach., Conclusions: By factoring in the variations in the spectral shape of ⟨ L ⟩ relative to SaO 2 , our self-calibrated algorithm enables accurate SaO 2 estimation, even in subjects with low SaO 2 levels., (© 2023 The Authors.)

Cortical spreading depolarization (CSD) is a neuropathological condition involving propagating waves of neuronal silence, and is related to multiple diseases, such as migraine aura, traumatic brain injury (TBI), stroke, and cardiac arrest, as well as poor outcome of patients. While CSDs of different severity share similar roots on the ion exchange level, they can lead to different vascular responses (namely spreading hyperemia and spreading ischemia). In this paper, we propose a mathematical model relating neuronal activities to predict vascular changes as measured with near-infrared spectroscopy (NIRS) and fMRI recordings, and apply it to the extreme case of CSD, where sustained near-complete neuronal depolarization is seen. We utilize three serially connected models (namely, ion exchange, neurovascular coupling, and hemodynamic model) which are described by differential equations. Propagating waves of ion concentrations, as well as the associated vasodynamics and hemodynamics, are simulated by solving these equations. Our proposed model predicts vasodynamics and hemodynamics that agree both qualitatively and quantitatively with experimental literature. Mathematical modeling and simulation offer a powerful tool to help understand the underlying mechanisms of CSD and help interpret the data. In addition, it helps develop novel monitoring techniques prior to data collection. Our simulated results strongly suggest that fMRI is unable to reliably distinguish between spreading hyperemia and spreading ischemia, while NIRS signals are substantially distinct in the two cases., Competing Interests: Declaration of competing interest The authors declare no conflicting interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Electroencephalography (EEG) and diffuse optical tomography (DOT) are imaging methods which are widely used for neuroimaging. While the temporal resolution of EEG is high, the spatial resolution is typically limited. DOT, on the other hand, has high spatial resolution, but the temporal resolution is inherently limited by the slow hemodynamics it measures. In our previous work, we showed using computer simulations that when using the results of DOT reconstruction as the spatial prior for EEG source reconstruction, high spatio-temporal resolution could be achieved. In this work, we experimentally validate the algorithm by alternatingly flashing two visual stimuli at a speed that is faster than the temporal resolution of DOT. We show that the joint reconstruction using both EEG and DOT clearly resolves the two stimuli temporally, and the spatial confinement is drastically improved in comparison to reconstruction using EEG alone., Competing Interests: Declaration of Competing Interest None, (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Recent work has noted a skin-color bias in existing pulse oximetry systems in their estimation of arterial oxygen saturation. Frequently, the algorithm used by these systems estimate a "ratio-of-ratios", called the "R-value", on their way to estimating the oxygen saturation. In this work, we focus on an "SNR-related" bias that is due to noise in measurements. We derive expressions for the SNR-related bias in R-value estimation, and observe how it scales with the signal-to-noise ratio (SNR). We show that the bias can arise at two steps of R-value estimation: in estimating the max and min of a pulsatile signal, and, additionally in taking ratios to estimate the R-value. We assess the bias resulting from the combination of the two steps, but also separate out contributions of each step. By doing so, we deduce that the bias induced in max and min estimation is likely to dominate. Because the SNR tends to get worse with higher melanin concentration, our result provides a sense of scaling of this bias with melanin concentration.

Significance: Using functional near-infrared spectroscopy (fNIRS) in bottlenose dolphins ( Tursiops truncatus ) could help to understand how echolocating animals perceive their environment and how they focus on specific auditory objects, such as fish, in noisy marine settings., Aim: To test the feasibility of near-infrared spectroscopy (NIRS) in medium-sized marine mammals, such as dolphins, we modeled the light propagation with computational tools to determine the wavelengths, optode locations, and separation distances that maximize sensitivity to brain tissue., Approach: Using frequency-domain NIRS, we measured the absorption and reduced scattering coefficient of dolphin sculp. We assigned muscle, bone, and brain optical properties from the literature and modeled light propagation in a spatially accurate and biologically relevant model of a dolphin head, using finite-element modeling. We assessed tissue sensitivities for a range of wavelengths (600 to 1700 nm), source-detector distances (50 to 120 mm), and animal sizes (juvenile model 25% smaller than adult)., Results: We found that the wavelengths most suitable for imaging the brain fell into two ranges: 700 to 900 nm and 1100 to 1150 nm. The optimal location for brain sensing positioned the center point between source and detector 30 to 50 mm caudal of the blowhole and at an angle 45 deg to 90 deg lateral off the midsagittal plane. Brain tissue sensitivity comparable to human measurements appears achievable only for smaller animals, such as juvenile bottlenose dolphins or smaller species of cetaceans, such as porpoises, or with source-detector separations ≫ 100    mm in adult dolphins., Conclusions: Brain measurements in juvenile or subadult dolphins, or smaller dolphin species, may be possible using specialized fNIRS devices that support optode separations of > 100    mm . We speculate that many measurement repetitions will be required to overcome hemodynamic signals originating predominantly from the muscle layer above the skull. NIRS measurements of muscle tissue are feasible today with source-detector separations of 50 mm, or even less., (© 2023 The Authors.)

Goal: Cerebrovascular impedance is modulated by a vasoactive autoregulative mechanism in response to changes in cerebral perfusion pressure. Characterization of impedance and the limits of autoregulation are important biomarkers of cerebral health. We developed a method to quantify impedance based on the spectral content of cerebral blood flow and volume at the cardiac frequency, measured with diffuse optical methods. Methods: In three non-human primates, we modulated cerebral perfusion pressure beyond the limits of autoregulation. Cerebral blood flow and volume were measured with diffuse correlation spectroscopy and near-infrared spectroscopy, respectively. Results: We show that impedance can be used to identify the lower and upper limits of autoregulation. Conclusions: This impedance method may be an alternative method to measure autoregulation and a way of assessing cerebral health non-invasively at the clinical bedside.

Significance: Cerebrovascular impedance (CVI) is related to cerebral autoregulation (CA), which is the mechanism of the brain to maintain near-constant cerebral blood flow (CBF) despite changes in cerebral perfusion pressure (CPP). Changes in blood vessel impedance enable the stabilization of blood flow. Due to the interplay between CVI and CA, assessment of CVI may enable quantification of CA and may serve as a biomarker for cerebral health., Aim: We developed a method to quantify CVI based on a combination of diffuse correlation spectroscopy (DCS) and continuous wave (CW) near-infrared spectroscopy (NIRS). Data on healthy human volunteers were used to validate the method., Approach: A combined high-speed DCS-NIRS system was developed, allowing for simultaneous, noninvasive blood flow, and volume measurements in the same tissue compartment. Blood volume was used as a surrogate measurement for blood pressure and CVI was calculated as the spectral ratio of blood volume and blood flow changes. This technique was validated on six healthy human volunteers undergoing postural changes to elicit CVI changes., Results: Averaged across the six subjects, a decrease in CVI was found for a head of bed (HOB) tilting of - 40    deg . These impedance changes were reversed when returning to the horizontal (0 deg) HOB baseline., Conclusions: We developed a combined DCS-NIRS system, which measures CBF and volume changes, which we demonstrate can be used to measure CVI. Using CVI as a metric of CA may be beneficial for assessing cerebral health, especially in patients where CPP is altered., (© 2023 The Authors.)

Objective: Intracranial pressure (ICP) is an important therapeutic target in many critical neuropathologies. The current tools for ICP measurements are invasive; hence, these are only selectively applied in critical cases where the benefits surpass the risks. To address the need for low-risk ICP monitoring, the authors developed a noninvasive alternative., Methods: The authors recently demonstrated noninvasive quantification of ICP in an animal model by using morphological analysis of microvascular cerebral blood flow (CBF) measured with diffuse correlation spectroscopy (DCS). The current prospective observational study expanded on this preclinical study by translating the method to pediatric patients. Here, the CBF features, along with mean arterial pressure (MAP) and heart rate (HR) data, were used to build a random decision forest, machine learning model for estimation of ICP; the results of this model were compared with those of invasive monitoring., Results: Fifteen patients (mean age ± SD [range] 9.8 ± 5.1 [0.3-17.5] years; median age [interquartile range] 11 [7.4] years; 10 males and 5 females) who underwent invasive neuromonitoring for any purpose were enrolled. Estimated ICP (ICPest) very closely matched invasive ICP (ICPinv), with a root mean square error (RMSE) of 1.01 mm Hg and 95% limit of agreement of ≤ 1.99 mm Hg for ICPinv 0.01-41.25 mm Hg. When the ICP range (ICPinv 0.01-29.05 mm Hg) was narrowed on the basis of the sample population, both RMSE and limit of agreement improved to 0.81 mm Hg and ≤ 1.6 mm Hg, respectively. In addition, 0.3% of the test samples for ICPinv ≤ 20 mm Hg and 5.4% of the test samples for ICPinv > 20 mm Hg had a limit of agreement > 5 mm Hg, which may be considered the acceptable limit of agreement for clinical validity of ICP sensing. For the narrower case, 0.1% of test samples for ICPinv ≤ 20 mm Hg and 1.1% of the test samples for ICPinv > 20 mm Hg had a limit of agreement > 5 mm Hg. Although the CBF features were crucial, the best prediction accuracy was achieved when these features were combined with MAP and HR data. Lastly, preliminary leave-one-out analysis showed model accuracy with an RMSE of 6 mm Hg and limit of agreement of ≤ 7 mm Hg., Conclusions: The authors have shown that DCS may enable ICP monitoring with additional clinical validation. The lower risk of such monitoring would allow ICP to be estimated for a wide spectrum of indications, thereby both reducing the use of invasive monitors and increasing the types of patients who may benefit from ICP-directed therapies.

As 3D bioprinting has grown as a fabrication technology, so too has the need for improved analytical methods to characterize engineered constructs. This is especially challenging for engineered tissues composed of hydrogels and cells, as these materials readily deform when trying to assess print fidelity and other properties non-destructively. Establishing that the 3D architecture of the bioprinted construct matches its intended anatomic design is critical given the importance of structure-function relationships in most tissue types. Here we report development of a multimaterial bioprinting platform with integrated optical coherence tomography for in situ volumetric imaging, error detection, and 3D reconstruction. We also report improvements to the freeform reversible embedding of suspended hydrogels bioprinting process through new collagen bioink compositions, gelatin microparticle support bath optical clearing, and optimized machine pathing. This enables quantitative 3D volumetric imaging with micron resolution over centimeter length scales, the ability to detect a range of print defect types within a 3D volume, and real-time imaging of the printing process at each print layer. These advances provide a comprehensive methodology for print quality assessment, paving the way toward the production and process control required for achieving regulatory approval and ultimately clinical translation of engineered tissues., (© 2022 IOP Publishing Ltd.)

Significance: Intracranial pressure (ICP) measurements are important for patient treatment but are invasive and prone to complications. Noninvasive ICP monitoring methods exist, but they suffer from poor accuracy, lack of generalizability, or high cost., Aim: We previously showed that cerebral blood flow (CBF) cardiac waveforms measured with diffuse correlation spectroscopy can be used for noninvasive ICP monitoring. Here we extend the approach to cardiac waveforms measured with near-infrared spectroscopy (NIRS)., Approach: Changes in hemoglobin concentrations were measured in eight nonhuman primates, in addition to invasive ICP, arterial blood pressure, and CBF changes. Features of average cardiac waveforms in hemoglobin and CBF signals were used to train a random forest (RF) regressor., Results: The RF regressor achieves a cross-validated ICP estimation of 0.937 r 2 , 2.703 - mm Hg 2 mean squared error (MSE), and 95% confidence interval (CI) of [ - 3.064    3.160 ]    mmHg on oxyhemoglobin concentration changes; 0.946 r 2 , 2.301 - mmHg 2 MSE, and 95% CI of [ - 2.841    2.866 ]    mmHg on total hemoglobin concentration changes; and 0.963 r 2 , 1.688    mmHg 2 MSE, and 95% CI of [ - 2.450    2.397 ]    mmHg on CBF changes., Conclusions: This study provides a proof of concept for the use of NIRS in noninvasive ICP estimation., (© 2022 The Authors.)

Diffuse correlation spectroscopy (DCS) has been widely explored for its ability to measure cerebral blood flow (CBF), however, mostly under the assumption that the human head is homogenous. In addition to CBF, knowledge of extracerebral layers, such as skull thickness, can be informative and crucial for patient with brain complications such as traumatic brain injuries. To bridge the gap, this study explored the feasibility of simultaneously extracting skull thickness and flow in the cortex layer using DCS. We validated a two-layer analytical model that assumed the skull as top layer with a finite thickness and the brain cortex as bottom layer with semi-infinite geometry. The model fitted for thickness of the top layer and flow of the bottom layer, while assumed other parameters as constant. The accuracy of the two-layer model was tested against the conventional single-layer model using measurements from custom made two-layer phantoms mimicking skull and brain. We found that the fitted top layer thickness at each source detector (SD) distance is correlated with the expected thickness. For the fitted bottom layer flow, the two-layer model fits relatively consistent flow across all top layer thicknesses. In comparison, the conventional one-layer model increasingly underestimates the bottom layer flow as top layer thickness increases. The overall accuracy of estimating first layer thickness and flow depends on the SD distance in relationship to first layer thickness. Lastly, we quantified the influence of uncertainties in the optical properties of each layer. We found that uncertainties in the optical properties only mildly influence the fitted thickness and flow. In this work we demonstrate the feasibility of simultaneously extracting of layer thickness and flow using a two-layer DCS model. Findings from this work may introduce a robust and cost-effective approach towards simultaneous bedside assessment of skull thickness and cerebral blood flow., Competing Interests: The authors have declared that no competing interests exist.

This report is the second part of a comprehensive two-part series aimed at reviewing an extensive and diverse toolkit of novel methods to explore brain health and function. While the first report focused on neurophotonic tools mostly applicable to animal studies, here, we highlight optical spectroscopy and imaging methods relevant to noninvasive human brain studies. We outline current state-of-the-art technologies and software advances, explore the most recent impact of these technologies on neuroscience and clinical applications, identify the areas where innovation is needed, and provide an outlook for the future directions., (© 2022 The Authors.)

Near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) measure cerebral hemodynamics, which in turn can be used to assess the cerebral metabolic rate of oxygen (CMRO 2 ) and cerebral autoregulation (CA). However, current mathematical models for CMRO 2 estimation make assumptions that break down for cerebral perfusion pressure (CPP)-induced changes in CA. Here, we performed preclinical experiments with controlled changes in CPP while simultaneously measuring NIRS and DCS at rest. We observed changes in arterial oxygen saturation (~10%) and arterial blood volume (~50%) with CPP, two variables often assumed to be constant in CMRO 2 estimations. Hence, we propose a general mathematical model that accounts for these variations when estimating CMRO 2 and validate its use for CA monitoring on our experimental data. We observed significant changes in the various oxygenation parameters, including the coupling ratio (CMRO 2 /blood flow) between regions of autoregulation and dysregulation. Our work provides an appropriate model and preliminary experimental evidence for the use of NIRS- and DCS-based tissue oxygenation and metabolism metrics for non-invasive diagnosis of CA health in CPP-altering neuropathologies.

Cerebral autoregulation ensures a stable average blood supply to brain tissue across steady state cerebral perfusion pressure (CPP) levels. Neurovascular coupling, in turn, relies on sufficient blood flow to meet neuronal demands during activation. These mechanisms break down in pathologies where extreme levels of CPP can cause dysregulation in cerebral blood flow. Here, we experimentally tested the influence of changes in CPP on neurovascular coupling in a hydrocephalus-type non-human primate model (n = 3). We recorded local neural and vascular evoked responses to a checkerboard visual stimulus, non-invasively, using electroencephalography and near-infrared spectroscopy respectively. The evoked signals showed changes in various waveform features in the visual evoked potentials and the hemodynamic responses, with CPP. We further used these signals to fit for a hemodynamic response function (HRF) to describe neurovascular coupling. We estimated n = 26 distinct HRFs at a subset of CPP values ranging from 40-120 mmHg across all subjects. The HRFs, when compared to a subject dependent healthy baseline (CPP 70-90 mmHg) HRF, showed significant changes in shape with increasing CPP (ρ CPP  = -0.55, p-value CPP  = 0.0049). Our study provides preliminary experimental evidence on the relationship between neurovascular coupling and CPP changes, especially when beyond the limits of static autoregulation.

The current technology for monitoring fetal wellbeing during child birth is cardiotocography. However, CTG has high false positive rates that lead to unnecessary emergency Cesarean deliveries and false negatives that result in birth injuries. To curtail these issues, fetal pulse oximetery has been a topic of interest for many decades. Fetal pulse oximetry would yield the oxygen saturation of the fetus in utero and provide a more robust marker for clinicians to make decisions about performing emergency Cesarean deliveries. Here, we present a review of biomedical optical developments related to transabdominal fetal pulse oximetery in the biophotonics field and the challenges that must be overcome to make transabdominal pulse oximetry a clinical reality., (© 2022 The Authors. Journal of Biophotonics published by Wiley-VCH GmbH.)

Acute stroke is associated with high morbidity and mortality. In the last decades, new therapies have been investigated with the aim of improving clinical outcomes in the acute phase post stroke onset. However, despite such advances, a large number of patients do not demonstrate improvement, furthermore, some unfortunately deteriorate. Thus, there is a need for additional treatments targeted to the individual patient. A potential therapeutic target is interventions to optimize cerebral perfusion guided by cerebral hemodynamic parameters such as dynamic cerebral autoregulation (dCA). This narrative led to the development of the INFOMATAS (Identifying New targets FOr Management And Therapy in Acute Stroke) project, designed to foster interventions directed towards understanding and improving hemodynamic aspects of the cerebral circulation in acute cerebrovascular disease states. This comprehensive review aims to summarize relevant studies on assessing dCA in patients suffering acute ischemic stroke, intracerebral haemorrhage, and subarachnoid haemorrhage. The review will provide to the reader the most consistent findings, the inconsistent findings which still need to be explored further and discuss the main limitations of these studies. This will allow for the creation of a research agenda for the use of bedside dCA information for prognostication and targeted perfusion interventions.

Developments in wearable human medical and sports health trackers has offered new solutions to challenges encountered by eco-physiologists attempting to measure physiological attributes in freely moving animals. Near-infrared spectroscopy (NIRS) is one such solution that has potential as a powerful physio-logging tool to assess physiology in freely moving animals. NIRS is a non-invasive optics-based technology, that uses non-ionizing radiation to illuminate biological tissue and measures changes in oxygenated and deoxygenated hemoglobin concentrations inside tissues such as skin, muscle, and the brain. The overall footprint of the device is small enough to be deployed in wearable physio-logging devices. We show that changes in hemoglobin concentration can be recorded from bottlenose dolphins and gray seals with signal quality comparable to that achieved in human recordings. We further discuss functionality, benefits, and limitations of NIRS as a standard tool for animal care and wildlife tracking for the marine mammal research community., Competing Interests: AF was employed by company Global Diving Research Sociedad Limitada. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ruesch, McKnight, Fahlman, Shinn-Cunningham and Kainerstorfer.)

About a third of babies are delivered by Cesarean section. There has been an increase in maternal deaths during labor due to complications with subsequent births after a C-section. Therefore, there is a clinical motivation to reduce the C-section rate. Current techniques are, however, inefficient at determining fetal distress leading to a high false positive rate for complications and ultimately a C-section. For the current study, Monte Carlo simulations were used to calculate the amount of signal received on a model of a pregnant mother, as well as, the percent of the signal that comes from the fetal layer. Models with and without a 1 mm amniotic fluid were compared and showed differing trends., (© 2021 The Authors. Journal of Biophotonics published by Wiley-VCH GmbH.)

Continuous measurements of haemodynamic and oxygenation changes in free living animals remain elusive. However, developments in biomedical technologies may help to fill this knowledge gap. One such technology is continuous-wave near-infrared spectroscopy (CW-NIRS)-a wearable and non-invasive optical technology. Here, we develop a marinized CW-NIRS system and deploy it on elite competition freedivers to test its capacity to function during deep freediving to 107 m depth. We use the oxyhaemoglobin and deoxyhaemoglobin concentration changes measured with CW-NIRS to monitor cerebral haemodynamic changes and oxygenation, arterial saturation and heart rate. Furthermore, using concentration changes in oxyhaemoglobin engendered by cardiac pulsation, we demonstrate the ability to conduct additional feature exploration of cardiac-dependent haemodynamic changes. Freedivers showed cerebral haemodynamic changes characteristic of apnoeic diving, while some divers also showed considerable elevations in venous blood volumes close to the end of diving. Some freedivers also showed pronounced arterial deoxygenation, the most extreme of which resulted in an arterial saturation of 25%. Freedivers also displayed heart rate changes that were comparable to diving mammals both in magnitude and patterns of change. Finally, changes in cardiac waveform associated with heart rates less than 40 bpm were associated with changes indicative of a reduction in vascular compliance. The success here of CW-NIRS to non-invasively measure a suite of physiological phenomenon in a deep-diving mammal highlights its efficacy as a future physiological monitoring tool for human freedivers as well as free living animals. This article is part of the theme issue 'Measuring physiology in free-living animals (Part II)'.

Sensory ecology and physiology of free-ranging animals is challenging to study but underpins our understanding of decision-making in the wild. Existing non-invasive human biomedical technology offers tools that could be harnessed to address these challenges. Functional near-infrared spectroscopy (fNIRS), a wearable, non-invasive biomedical imaging technique measures oxy- and deoxyhaemoglobin concentration changes that can be used to detect localized neural activation in the brain. We tested the efficacy of fNIRS to detect cortical activation in grey seals ( Halichoerus grypus ) and identify regions of the cortex associated with different senses (vision, hearing and touch). The activation of specific cerebral areas in seals was detected by fNIRS in responses to light (vision), sound (hearing) and whisker stimulation (touch). Physiological parameters, including heart and breathing rate, were also extracted from the fNIRS signal, which allowed neural and physiological responses to be monitored simultaneously. This is, to our knowledge, the first time fNIRS has been used to detect cortical activation in a non-domesticated or laboratory animal. Because fNIRS is non-invasive and wearable, this study demonstrates its potential as a tool to quantitatively investigate sensory perception and brain function while simultaneously recording heart rate, tissue and arterial oxygen saturation of haemoglobin, perfusion changes and breathing rate in free-ranging animals. This article is part of the theme issue 'Measuring physiology in free-living animals (Part I)'.

The brain's ability to maintain cerebral blood flow approximately constant despite cerebral perfusion pressure changes is known as cerebral autoregulation (CA) and is governed by vasoconstriction and vasodilation. Cerebral perfusion pressure is defined as the pressure gradient between arterial blood pressure and intracranial pressure. Measuring CA is a challenging task and has created a variety of evaluation methods, which are often categorized as static and dynamic CA assessments. Because CA is quantified as the performance of a regulatory system and no physical ground truth can be measured, conflicting results are reported. The conflict further arises from a lack of healthy volunteer data with respect to cerebral perfusion pressure measurements and the variety of diseases in which CA ability is impaired, including stroke, traumatic brain injury and hydrocephalus. To overcome these differences, we present a healthy non-human primate model in which we can control the ability to autoregulate blood flow through the type of anesthesia (isoflurane vs fentanyl). We show how three different assessment methods can be used to measure CA impairment, and how static and dynamic autoregulation compare under challenges in intracranial pressure and blood pressure. We reconstructed Lassen's curve for two groups of anesthesia, where only the fentanyl anesthetized group yielded the canonical shape. Cerebral perfusion pressure allowed for the best distinction between the fentanyl and isoflurane anesthetized groups. The autoregulatory response time to induced oscillations in intracranial pressure and blood pressure, measured as the phase lag between intracranial pressure and blood pressure, was able to determine autoregulatory impairment in agreement with static autoregulation. Static and dynamic CA both show impairment in high dose isoflurane anesthesia, while low isoflurane in combination with fentanyl anesthesia maintains CA, offering a repeatable animal model for CA studies., Competing Interests: The authors have declared that no competing interests exist.

Significance: Electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) are both commonly used methodologies for neuronal source reconstruction. While EEG has high temporal resolution (millisecond-scale), its spatial resolution is on the order of centimeters. On the other hand, in comparison to EEG, fNIRS, or diffuse optical tomography (DOT), when used for source reconstruction, can achieve relatively high spatial resolution (millimeter-scale), but its temporal resolution is poor because the hemodynamics that it measures evolve on the order of several seconds. This has important neuroscientific implications: e.g., if two spatially close neuronal sources are activated sequentially with only a small temporal separation, single-modal measurements using either EEG or DOT alone would fail to resolve them correctly. Aim: We attempt to address this issue by performing joint EEG and DOT neuronal source reconstruction. Approach: We propose an algorithm that utilizes DOT reconstruction as the spatial prior of EEG reconstruction, and demonstrate the improvements using simulations based on the ICBM152 brain atlas. Results: We show that neuronal sources can be reconstructed with higher spatiotemporal resolution using our algorithm than using either modality individually. Further, we study how the performance of the proposed algorithm can be affected by the locations of the neuronal sources, and how the performance can be enhanced by improving the placement of EEG electrodes and DOT optodes. Conclusions: We demonstrate using simulations that two sources separated by 2.3-3.3 cm and 50 ms can be recovered accurately using the proposed algorithm by suitably combining EEG and DOT, but not by either in isolation. We also show that the performance can be enhanced by optimizing the electrode and optode placement according to the locations of the neuronal sources., (© 2021 The Authors.)

Intracranial pressure (ICP) is typically measured invasively through a sensor placed inside the brain or a needle inserted into the spinal canal, limiting the patient population on which this assessment can be performed. Currently, non-invasive methods are limited due to lack of sensitivity and thus only apply to extreme cases of increased ICP, instead of use in general clinical practice. We demonstrate a novel application for near-infrared spectroscopy (NIRS) to accurately estimate ICP changes over time. Using a non-human primate (Rhesus Macaque) model, we collected optical data while we induced ICP oscillations at multiple ICP levels obtained by manipulating the height of a fluid column connected via a catheter to the lateral ventricle. Hemodynamic responses to ICP changes were measured at the occipital pole and compared to changes detected by a conventional intraparenchymal ICP probe. We demonstrate that hemoglobin concentrations are highly correlated with induced ICP oscillations and that this response is frequency dependent. We translated the NIRS data into non-invasive ICP measurements via a fitted non-parametric transfer function, demonstrating a match in both magnitude and time alignment with an invasively measured reference. Our results demonstrate that NIRS has the potential for non-invasive ICP monitoring.

Measuring intracranial pressure (ICP) is necessary for the treatment of severe head injury but measurement systems are highly invasive and introduce risk of infection and complications. We developed a non-invasive alternative for quantifying ICP using measurements of cerebral blood flow (CBF) by diffuse correlation spectroscopy. The recorded cardiac pulsation waveform in CBF undergoes morphological changes in response to ICP changes. We used the pulse shape to train a randomized regression forest to estimate the underlying ICP and demonstrate in five non-human primates that DCS-based estimation can explain over 90% of the variance in invasively measured ICP., Competing Interests: The authors declare no conflict of interest., (© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Although shape perception is primarily considered a function of the ventral visual pathway, previous research has shown that both dorsal and ventral pathways represent shape information. Here, we examine whether the shape-selective electrophysiological signals observed in dorsal cortex are a product of the connectivity to ventral cortex or are independently computed. We conducted multiple EEG studies in which we manipulated the input parameters of the stimuli so as to bias processing to either the dorsal or ventral visual pathway. Participants viewed displays of common objects with shape information parametrically degraded across five levels. We measured shape sensitivity by regressing the amplitude of the evoked signal against the degree of stimulus scrambling. Experiment 1, which included grayscale versions of the stimuli, served as a benchmark establishing the temporal pattern of shape processing during typical object perception. These stimuli evoked broad and sustained patterns of shape sensitivity beginning as early as 50 msec after stimulus onset. In Experiments 2 and 3, we calibrated the stimuli such that visual information was delivered primarily through parvocellular inputs, which mainly project to the ventral pathway, or through koniocellular inputs, which mainly project to the dorsal pathway. In the second and third experiments, shape sensitivity was observed, but in distinct spatio-temporal configurations from each other and from that elicited by grayscale inputs. Of particular interest, in the koniocellular condition, shape selectivity emerged earlier than in the parvocellular condition. These findings support the conclusion of distinct dorsal pathway computations of object shape, independent from the ventral pathway.

We recently reported the use of optical imaging technology to quantify facial plethora in endogenous Cushing syndrome (CS). In the present study, we studied a larger cohort of patients with Cushing disease (CD) and examined water content fraction as well as blood volume fraction as bio-optic markers for determining the efficacy of this methodology as a predictor of lasting remission after surgery for CS. We imaged 49 patients before and after transsphenoidal surgery (TSS) for Cushing disease (CD); 22 patients were also seen at 3-6 months, and 13 patients 12 months post-operatively. On all patients, we used multi-spectral imaging (MSI) to evaluate hemodynamic distributions as well as water content at a specific area of the face. We found a decrease in blood volume fraction after vs. before surgical treatment in the tested facial area in 37 of the 40 patients, as determined with biochemical markers (p<0.001). All patients that were followed up for up to 12 months showed the same decrease from preoperative values and they remained in remission from CD. We conclude that MSI can be used for the evaluation of remission from CD, at least in the immediate post-operative period and up to one year after surgery. The use of this technology can supplement biochemical and other testing for the evaluation of the various treatment modalities available for patients with CD., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

In breast cancer diagnosis and therapy monitoring, there is a need for frequent, noninvasive disease progression evaluation. Breast tumors differ from healthy tissue in mechanical stiffness as well as optical properties, which allows optical methods to detect and monitor breast lesions noninvasively. Spatial frequency-domain imaging (SFDI) is a reflectance-based diffuse optical method that can yield two-dimensional images of absolute optical properties of tissue with an inexpensive and portable system, although depth penetration is limited. Since the absorption coefficient of breast tissue is relatively low and the tissue is quite flexible, there is an opportunity for compression of tissue to bring stiff, palpable breast lesions within the detection range of SFDI. Sixteen breast tissue-mimicking phantoms were fabricated containing stiffer, more highly absorbing tumor-mimicking inclusions of varying absorption contrast and depth. These phantoms were imaged with an SFDI system at five levels of compression. An increase in absorption contrast was observed with compression, and reliable detection of each inclusion was achieved when compression was sufficient to bring the inclusion center within ∼12  mm of the phantom surface. At highest compression level, contrasts achieved with this system were comparable to those measured with single source-detector near-infrared spectroscopy., ((2017) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).)

The mechanism that maintains a stable blood flow in the brain despite changes in cerebral perfusion pressure (CPP), and therefore guaranties a constant supply of oxygen and nutrients to the neurons, is known as cerebral autoregulation (CA). In a certain range of CPP, blood flow is mediated by a vasomotor adjustment in vascular resistance through dilation of blood vessels. CA is known to be impaired in diseases like traumatic brain injury, Parkinson's disease, stroke, hydrocephalus and others. If CA is impaired, blood flow and pressure changes are coupled and the oxygen supply might be unstable. Lassen's blood flow autoregulation curve describes this mechanism, where a plateau of stable blood flow in a specific range of CPP corresponds to intact autoregulation. Knowing the limits of this plateau and maintaining CPP within these limits can improve patient outcome. Since CPP is influenced by both intracranial pressure and arterial blood pressure, long term changes in either can lead to autoregulation impairment. Non-invasive methods for monitoring blood flow autoregulation are therefore needed. We propose to use Near infrared spectroscopy (NIRS) to fill this need. NIRS is an optical technique, which measures microvascular changes in cerebral hemoglobin concentration. We pe erformed experiments on non-human primates during exsanguination to demonstrate that the limits of blood flow autoregulation can be accessed with NIRS.

We present a near-infrared spectroscopy (NIRS) study of local hemodynamics in the breast and the brain (prefrontal cortex) of healthy volunteers in a protocol involving periodic perturbations to the systemic arterial blood pressure. These periodic perturbations were achieved by cyclic inflation (to a pressure of 200 mmHg) and deflation (at frequencies of 0.046, 0.056, 0.063, 0.071, and 0.083 Hz) of two pneumatic cuffs wrapped around the subject’s thighs. As a result of these systemic perturbations, the concentrations of deoxy- and oxyhemoglobin in tissue (D and O , respectively) oscillate at the set frequency. We found that the oscillations of D and O in breast tissue are in-phase at all frequencies considered, a result that we attribute to dominant contributions from blood volume oscillations. In contrast, D and O oscillations in brain tissue feature a frequency-dependent phase difference, which we attribute to significant contributions from cerebral blood flow oscillations. Frequency-resolved measurements of D and O oscillations are exploited by the technique of coherent hemodynamics spectroscopy for the assessment of cerebrovascular parameters and cerebral autoregulation. We show the relevant physiological information content of NIRS measurements of oscillatory hemodynamics, which have qualitatively distinct features in the healthy breast and healthy brain.

We present a study of the bilateral symmetry of human breast hemoglobin saturation maps measured with a broadband optical mammography instrument. We have imaged 21 patients with unilateral breast cancer, 32 patients with unilateral benign lesions, and 27 healthy patients. An image registration process was applied to the bilateral hemoglobin saturation (SO 2 SO2 ) images by assigning each pixel to the low, middle, or high range of SO 2 SO2 values, where the thresholds for the categories were the 15th and 85th percentiles of the individual saturation range. The Dice coefficient, which is a measure of similarity, was calculated for each patient’s pair of right and left breast SO 2 SO2 images. The invasive cancer patients were found to have an average Dice coefficient value of 0.55±0.07 0.55±0.07 , which was significantly lower than the benign and healthy groups (0.61±0.11 0.61±0.11 and 0.62±0.12 0.62±0.12 , respectively). Although differences were seen in a group analysis, the healthy patient Dice coefficients spanned a wide range, limiting the diagnostic capabilities of this SO 2 SO2 symmetry analysis on an individual basis. Our results suggest that for assessing the SO 2 SO2 contrast of breast lesions, it may be better to select a reference tissue in the ipsilateral rather than the contralateral breast.

We present a quantitative analysis of dynamic diffuse optical measurements to obtain oxygen saturation of hemoglobin in volume oscillating compartments. We used a phasor representation of oscillatory hemodynamics at the heart rate and respiration frequency to separate the oscillations of tissue concentrations of oxyhemoglobin (O) and deoxyhemoglobin (D) into components due to blood volume (subscript V V ) and blood flow (subscript F F ): O=O V +O F O=OV+OF , D=D V +D F D=DV+DF . This is achieved by setting the phase angle Arg(O F )−Arg(O) Arg(OF)−Arg(O) , which can be estimated by a hemodynamic model that we recently developed. We found this angle to be −72  deg −72  deg for the cardiac pulsation at 1 Hz, and −7  deg −7  deg for paced breathing at 0.1 Hz. Setting this angle, we can obtain the oxygen saturation of hemoglobin of the volume-oscillating vascular compartment, S V =|O V |/(|O V |+|D V |) SV=|OV|/(|OV|+|DV|) . We demonstrate this approach with cerebral near-infrared spectroscopy measurements on healthy volunteers at rest (n=4 n=4 ) and during 0.1 Hz paced breathing (n=3 n=3 ) with a 24-channel system. Rest data at the cardiac frequency were used to calculate the arterial saturation, S (a) S(a) ; over all subjects and channels, we found ⟨S V ⟩=⟨S (a) ⟩=0.96±0.02 ⟨SV⟩=⟨S(a)⟩=0.96±0.02 . In the case of paced breathing, we found ⟨S V ⟩=0.66±0.14 ⟨SV⟩=0.66±0.14 , which reflects venous-dominated hemodynamics at the respiratory frequency.

We present a continuous-wave instrument for non-invasive diffuse optical imaging of the breast in a parallel-plate transmission geometry. The instrument measures continuous spectra in the wavelength range 650-1000 nm, with an intensity noise level <1.5% and a spatial sampling rate of 5 points/cm in the x- and y-directions. We collect the optical transmission at four locations, one collinear and three offset with respect to the illumination optical fiber, to recover the depth of optical inhomogeneities in the tissue. We imaged a tissue-like, breast shaped, silicone phantom (6 cm thick) with two embedded absorbing structures: a black circle (1.7 cm in diameter) and a black stripe (3 mm wide), designed to mimic a tumor and a blood vessel, respectively. The use of a spatially multiplexed detection scheme allows for the generation of on-axis and off-axis projection images simultaneously, as opposed to requiring multiple scans, thus decreasing scan-time and motion artifacts. This technique localizes detected inhomogeneities in 3D and accurately assigns their depth to within 1 mm in the ideal conditions of otherwise homogeneous tissue-like phantoms. We also measured induced hemodynamic changes in the breast of a healthy human subject at a selected location (no scanning). We applied a cyclic, arterial blood pressure perturbation by alternating inflation (to a pressure of 200 mmHg) and deflation of a pneumatic cuff around the subject's thigh at a frequency of 0.05 Hz, and measured oscillations with amplitudes up to 1 μM and 0.2 μM in the tissue concentrations of oxyhemoglobin and deoxyhemoglobin, respectively. These hemodynamic oscillations provide information about the vascular structure and functional integrity in tissue, and may be used to assess healthy or abnormal perfusion in a clinical setting.

In this work, we are proposing an extension of a recent hemodynamic model (Fantini, 2014a), which was developed within the framework of a novel approach to the study of tissue hemodynamics, named coherent hemodynamics spectroscopy (CHS). The previous hemodynamic model, from a signal processing viewpoint, treats the tissue microvasculature as a linear time-invariant system, and considers changes of blood volume, capillary blood flow velocity and the rate of oxygen diffusion as inputs, and the changes of oxy-, deoxy-, and total hemoglobin concentrations (measured in near infrared spectroscopy) as outputs. The model has been used also as a forward solver in an inversion procedure to retrieve quantitative parameters that assess physiological and biological processes such as microcirculation, cerebral autoregulation, tissue metabolic rate of oxygen, and oxygen extraction fraction. Within the assumption of "small" capillary blood flow velocity oscillations the model showed that the capillary and venous compartments "respond" to this input as low pass filters, characterized by two distinct impulse response functions. In this work, we do not make the assumption of "small" perturbations of capillary blood flow velocity by solving without approximations the partial differential equation that governs the spatio-temporal behavior of hemoglobin saturation in capillary and venous blood. Preliminary comparison between the linear time-invariant model and the extended model (here identified as nonlinear model) are shown for the relevant parameters measured in CHS as a function of the oscillation frequency (CHS spectra). We have found that for capillary blood flow velocity oscillations with amplitudes up to 10% of the baseline value (which reflect typical scenarios in CHS), the discrepancies between CHS spectra obtained with the linear and nonlinear models are negligible. For larger oscillations (~50%) the linear and nonlinear models yield CHS spectra with differences within typical experimental errors, but further investigation is needed to assess the effect of these differences. Flow oscillations larger than 10-20% are not typically induced in CHS; therefore, the results presented in this work indicate that a linear hemodynamic model, combined with a method to elicit controlled hemodynamic oscillations (as done for CHS), is appropriate for the quantitative assessment of cerebral microcirculation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Cerebral autoregulation (CA) is the mechanism that allows the brain to maintain a stable blood flow despite changes in blood pressure. Dynamic CA can be quantified based on continuous measurements of systemic mean arterial pressure (MAP) and global cerebral blood flow. Here, we show that dynamic CA can be quantified also from local measurements that are sensitive to the microvasculature. We used near-infrared spectroscopy (NIRS) to measure temporal changes in oxy- and deoxy-hemoglobin concentrations in the prefrontal cortex of 11 human subjects. A novel hemodynamic model translates those changes into changes of cerebral blood volume and blood flow. The interplay between them is described by transfer function analysis, specifically by a high-pass filter whose cutoff frequency describes the autoregulation efficiency. We have used pneumatic thigh cuffs to induce MAP perturbation by a fast release during rest and during hyperventilation, which is known to enhance autoregulation. Based on our model, we found that the autoregulation cutoff frequency increased during hyperventilation in comparison to normal breathing in 10 out of 11 subjects, indicating a greater autoregulation efficiency. We have shown that autoregulation can reliably be measured noninvasively in the microvasculature, opening up the possibility of localized CA monitoring with NIRS.

This study reports the optical characterization and quantitative oximetry of human breast cancer using spectrally-resolved images collected with a broadband, continuous-wave optical mammography instrument. On twenty-six cancer patients, we collected two-dimensional optical mammograms and created maps of the concentrations of hemoglobin, water, and lipids, as well as the oxygen saturation of hemoglobin. For each cancerous breast, we analyzed the difference between the tumor region (as identified by x-ray and optical mammography) and the remainder of breast tissue. With respect to the surrounding tissue, we found that cancer regions have significantly higher concentrations of total hemoglobin (+2.4 ± 0.4 μM) and water (+7 ± 1% v/v), and significantly lower lipid concentration (8 ± 2% v/v) and oxygen saturation of hemoglobin (5 ± 1%). We also found a significant correlation between the tumor optical contrast and the grade of breast cancer as quantified by the Nottingham histologic score; this demonstrates how optical signatures may be representative of metabolic and morphological features, as well as the aggressive potential of the tumor.

Coherent Hemodynamics Spectroscopy (CHS) is a technique based on inducing cerebral hemodynamic oscillations at multiple frequencies, measuring them with near-infrared spectroscopy (NIRS), and analyzing them with a hemodynamic model to obtain physiological information such as blood transit times in the microvasculature and the autoregulation cutoff frequency. We have previously demonstrated that such oscillations can be induced one frequency at a time. Here we demonstrate that CHS can be performed by a single inflation of two pneumatic thigh cuffs (duration: 2 min; pressure: 200 mmHg), whose sudden release produces a step response in systemic arterial blood pressure that lasts for ~20 s and induces cerebral hemodynamics that contain all the frequency information necessary for CHS. Following a validation study on simulated data, we performed measurements on human subjects with this new method based on a single occlusion/release of the thigh cuffs and with the previous method based on sequential sets of cyclic inflation/deflation one frequency at a time, and demonstrated that the two methods yield the same CHS spectra and the same physiological parameters (within measurement errors). The advantages of the new method presented here are that CHS spectra cover the entire bandwidth of the induced hemodynamic response, they are measured over ~20 s thus better satisfying the requirement of time invariance of physiological conditions, and they can be measured every ~2.5 min thus achieving finer temporal sampling in monitoring applications.

We present a pilot clinical application of coherent hemodynamics spectroscopy (CHS), a technique to investigate cerebral hemodynamics at the microcirculatory level. CHS relies on frequency-resolved measurements of induced cerebral hemodynamic oscillations that are measured with near-infrared spectroscopy (NIRS) and analyzed with a hemodynamic model. We have used cyclic inflation (200 mmHg) and deflation of a pneumatic cuff placed around the subject's thigh at seven frequencies in the range of 0.03 to 0.17 Hz to generate CHS spectra and to obtain a set of physiological parameters that include the blood transit times in the cerebral microcirculation, the cutoff frequency for cerebral autoregulation, and blood volume ratios across the three different compartments. We have investigated five hemodialysis patients, during the hemodialysis procedure, and six healthy subjects. We have found that the blood transit time in the cerebral microcirculation is significantly longer in hemodialysis patients with respect to healthy subjects. No significant differences were observed between the two groups in terms of autoregulation efficiency and blood volume ratios. The demonstration of the applicability of CHS in a clinical setting and its sensitivity to the highly important cerebral microcirculation may open up new opportunities for NIRS applications in research and in medical diagnostics and monitoring.

Rationale and Objectives: Perturbations in cerebral blood volume (CBV), blood flow (CBF), and metabolic rate of oxygen (CMRO2) lead to associated changes in tissue concentrations of oxy- and deoxy-hemoglobin (ΔO and ΔD), which can be measured by near-infrared spectroscopy (NIRS). A novel hemodynamic model has been introduced to relate physiological perturbations and measured quantities. We seek to use this model to determine functional traces of cbv(t) and cbf(t) - cmro2(t) from time-varying NIRS data, and cerebrovascular physiological parameters from oscillatory NIRS data (lowercase letters denote the relative changes in CBV, CBF, and CMRO2 with respect to baseline). Such a practical implementation of a quantitative hemodynamic model is an important step toward the clinical translation of NIRS., Materials and Methods: In the time domain, we have simulated O(t) and D(t) traces induced by cerebral activation. In the frequency domain, we have performed a new analysis of frequency-resolved measurements of cerebral hemodynamic oscillations during a paced breathing paradigm., Results: We have demonstrated that cbv(t) and cbf(t) - cmro2(t) can be reliably obtained from O(t) and D(t) using the model, and that the functional NIRS signals are delayed with respect to cbf(t) - cmro2(t) as a result of the blood transit time in the microvasculature. In the frequency domain, we have identified physiological parameters (e.g., blood transit time, cutoff frequency of autoregulation) that can be measured by frequency-resolved measurements of hemodynamic oscillations., Conclusions: The ability to perform noninvasive measurements of cerebrovascular parameters has far-reaching clinical implications. Functional brain studies rely on measurements of CBV, CBF, and CMRO2, whereas the diagnosis and assessment of neurovascular disorders, traumatic brain injury, and stroke would benefit from measurements of local cerebral hemodynamics and autoregulation., (Copyright © 2014 AUR. Published by Elsevier Inc. All rights reserved.)

We report an experimental validation and applications of the new hemodynamic model presented in the companion article (Fantini, 2014-this issue) both in the frequency domain and in the time domain. In the frequency domain, we have performed diffuse optical measurements for coherent hemodynamics spectroscopy (CHS) on the brain and calf muscle of human subjects, showing that the hemodynamic model predictions (both in terms of spectral shapes and absolute spectral values) are confirmed experimentally. We show how the quantitative analysis based on the new model allows for autoregulation measurements from brain data, and provides an analytical description of near-infrared spiroximetry from muscle data. In the time domain, we have used data from the literature to perform a comparison between brain activation signals measured with functional near-infrared spectroscopy (fNIRS) or with blood oxygenation level dependent (BOLD) fMRI, and the corresponding signals predicted by the new model. This comparison shows an excellent agreement between the model predictions and the reported fNIRS and BOLD fMRI signals. This new hemodynamic model provides a valuable tool for brain studies with hemodynamic-based techniques., (Copyright © 2013 Elsevier Inc. All rights reserved.)