Sensitivity analysis of transabdominal fetal pulse oximetry using MRI-based simulations.

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.

Cerebral hemodynamic and systemic physiological changes in trained freedivers completing sled-assisted dives to two different depths.

While 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 (SpO2), and 3) heart rate during breath-hold diving without confounding effects of exercise were investigated. Six freedivers (51.0 ± 12.6 years; mean ± s.d.), instrumented with continuous-wave near-infrared spectroscopy for monitoring cerebral hemodynamic and oxygenation measurements, heart rate and SpO2, 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 SpO2 due to lung expansion. While SpO2 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.

Evaluating feasibility of functional near-infrared spectroscopy in dolphins.

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.

Clinical translation of noninvasive intracranial pressure sensing with diffuse correlation spectroscopy.

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.

Cerebrovascular impedance estimation with near-infrared and diffuse correlation spectroscopy.

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.

In situvolumetric imaging and analysis of FRESH 3D bioprinted constructs using optical coherence tomography.

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 forin situvolumetric 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.

Using near-infrared spectroscopy and a random forest regressor to estimate intracranial pressure.

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.

Non-Invasive Spectroscopy for Measuring Cerebral Tissue Oxygenation and Metabolism as a Function of Cerebral Perfusion Pressure.

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 (CMRO2) and cerebral autoregulation (CA). However, current mathematical models for CMRO2 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 CMRO2 estimations. Hence, we propose a general mathematical model that accounts for these variations when estimating CMRO2 and validate its use for CA monitoring on our experimental data. We observed significant changes in the various oxygenation parameters, including the coupling ratio (CMRO2/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.

Erratum: Estimating intracranial pressure using pulsatile cerebral blood flow measured with diffuse correlation spectroscopy: erratum.

[This corrects the article on p. 1462 in vol. 11, PMID: 32206422.].

Changes in neurovascular coupling with cerebral perfusion pressure indicate a link to cerebral autoregulation.

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 (ρCPP = -0.55, p-valueCPP = 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.

When the human brain goes diving: using near-infrared spectroscopy to measure cerebral and systemic cardiovascular responses to deep, breath-hold diving in elite freedivers.

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)'.

Shining new light on sensory brain activation and physiological measurement in seals using wearable optical technology.

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)'.

Comparison of static and dynamic cerebral autoregulation under anesthesia influence in a controlled animal model.

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.

Near-Infrared Spectroscopy as a Tool for Marine Mammal Research and Care.

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.

Estimating intracranial pressure using pulsatile cerebral blood flow measured with diffuse correlation spectroscopy.

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.

Fluctuations in intracranial pressure can be estimated non-invasively using near-infrared spectroscopy in non-human primates.

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.