SignificanceA shortcoming of the routine clinical use of diffuse optics (DO) in the injured head has been that the results from commercial near-infrared spectroscopy-based devices are not reproducible, often give physiologically invalid values, and differ among systems. Besides the limitations due to the physics of continuous-wave light sources, one culprit is the head heterogeneity and the underlying morphological and functional abnormalities of the probed tissue.AimThe aim is to investigate the effect that different tissue alterations in the damaged head have on DO signals and provide guidelines to avoid data misinterpretation.ApproachDO measurements and computed tomography scans were acquired on brain-injured patients. The relationship between the signals and the underlying tissue types was classified on a case-by-case basis.ResultsExamples and suggestions to establish quality control routines were provided. The findings suggested guidelines for carrying out DO measurements and speculations toward improved devices.ConclusionsWe advocate for the standardization of the DO measurements to secure a role for DO in neurocritical care. We suggest that blind measurements are unacceptably problematic due to confounding effects and care using a priori and a posteriori quality control routines that go beyond an assessment of the signal-to-noise ratio that is typically utilized.
Time domain diffuse correlation spectroscopy (td-DCS), has been proposed as a method that can increase the sensitivity of DCS for detecting blood flow index (BFI) in deep tissue. Several important parameters including the instrument response function (IRF), gate start time, gate width, and source-detector separation (SDS) must be taken into consideration. In our study, we characterized td-DCS system at three different SDS values and assessed each SDS's ability to detect dynamic changes of blood flow caused by moving red blood cells during cuff occlusion.
SignificanceThe optical measurement of cerebral oxygen metabolism was evaluated.AimCompare optically derived cerebral signals to the electroencephalographic bispectral index (BIS) sensors to monitor propofol-induced anesthesia during surgery.ApproachRelative cerebral metabolic rate of oxygen (rCMRO2) and blood flow (rCBF) were measured by time-resolved and diffuse correlation spectroscopies. Changes were tested against the relative BIS (rBIS) ones. The synchronism in the changes was also assessed by the R-Pearson correlation.ResultsIn 23 measurements, optically derived signals showed significant changes in agreement with rBIS: during propofol induction, rBIS decreased by 67% [interquartile ranges (IQR) 62% to 71%], rCMRO2 by 33% (IQR 18% to 46%), and rCBF by 28% (IQR 10% to 37%). During recovery, a significant increase was observed for rBIS (48%, IQR 38% to 55%), rCMRO2 (29%, IQR 17% to 39%), and rCBF (30%, IQR 10% to 44%). The significance and direction of the changes subject-by-subject were tested: the coupling between the rBIS, rCMRO2, and rCBF was witnessed in the majority of the cases (14/18 and 12/18 for rCBF and 19/21 and 13/18 for rCMRO2 in the initial and final part, respectively). These changes were also correlated in time (R > 0.69 to R = 1, p-values < 0.05).ConclusionsOptics can reliably monitor rCMRO2 in such conditions.
Significance: Multi-laboratory initiatives are essential in performance assessment and standardization—crucial for bringing biophotonics to mature clinical use—to establish protocols and develop reference tissue phantoms that all will allow universal instrument comparison.
Aim: The largest multi-laboratory comparison of performance assessment in near-infrared diffuse optics is presented, involving 28 instruments and 12 institutions on a total of eight experiments based on three consolidated protocols (BIP, MEDPHOT, and NEUROPT) as implemented on three kits of tissue phantoms. A total of 20 synthetic indicators were extracted from the dataset, some of them defined here anew.
Approach: The exercise stems from the Innovative Training Network BitMap funded by the European Commission and expanded to include other European laboratories. A large variety of diffuse optics instruments were considered, based on different approaches (time domain/frequency domain/continuous wave), at various stages of maturity and designed for different applications (e.g., oximetry, spectroscopy, and imaging).
Results: This study highlights a substantial difference in hardware performances (e.g., nine decades in responsivity, four decades in dark count rate, and one decade in temporal resolution). Agreement in the estimates of homogeneous optical properties was within 12% of the median value for half of the systems, with a temporal stability of <5 % over 1 h, and day-to-day reproducibility of <3 % . Other tests encompassed linearity, crosstalk, uncertainty, and detection of optical inhomogeneities.
Conclusions: This extensive multi-laboratory exercise provides a detailed assessment of near-infrared Diffuse optical instruments and can be used for reference grading. The dataset—available soon in an open data repository—can be evaluated in multiple ways, for instance, to compare different analysis tools or study the impact of hardware implementations.
One sedative drug to induce anesthesia during surgery is propofol. It diminishes the cerebral metabolic rate of oxygen (CMRO2), preventing memory formation and is coupled with a decrease in the cerebral blood flow (CBF). Anesthesia depth is commonly monitored by the bispectral index (BIS) to avoid awareness. Optical hybrid near-infrared spectroscopies have the potential to assess CMRO2 and other physiological signals (i.e. CBF). Optical signals acquired alongside BIS in surgeries were compared to it and provided additional information. Overall, agreement was found at different levels (group analysis, single subject analysis and simultaneity in time of changes).
Hybrid device for the study of blood flow index and hemoglobins concentrations changes was developed. Diffuse correlation spectroscopy and time-resolved near-infrared spectroscopy were applied to study brain hemodynamics of healthy adults human during the Valsalva maneuver.
Performance assessment and standardization are indispensable for instruments of clinical relevance in general and clinical instrumentation based on photon migration/diffuse optics in particular. In this direction, a multi-laboratory exercise was initiated with the aim of assessing and comparing their performances. 29 diffuse optical instruments belonging to 11 partner institutions of a European level Marie Curie Consortium BitMap1 were considered for this exercise. The enrolled instruments covered different approaches (continuous wave, CW; frequency domain, FD; time domain, TD and spatial frequency domain imaging, SFDI) and applications (e.g. mammography, oximetry, functional imaging, tissue spectroscopy). 10 different tests from 3 well-accepted protocols, namely, the MEDPHOT2 , the BIP3 , and the nEUROPt4 protocols were chosen for the exercise and the necessary phantoms kits were circulated across labs and institutions enrolled in the study. A brief outline of the methodology of the exercise is presented here. Mainly, the design of some of the synthetic descriptors, (single numeric values used to summarize the result of a test and facilitate comparison between instruments) for some of the tests will be discussed.. Future actions of the exercise aim at deploying these measurements onto an open data repository and investigating common analysis tools for the whole dataset.
We utilized time-domain diffuse correlation spectroscopy (TD-DCS) to quantify depth-resolved blood flow changes for in vivo experiments on arm and forehead adult humans. We illustrated that conventional TD-DCS processing is incapable of estimating blood flow changes at short source-detector separations, as expected. To tackle this problem, we introduced a novel model. We recovered the relative blood flow index of the forearm muscle during the cuff occlusion challenge and human forehead under variable pressure accurately.
We apply time-domain diffuse correlation spectroscopy (TD DCS) to quantify dynamics in samples with mixed dynamics, containing both static and dynamic scatterers. We demonstrate that standard TD DCS processing is incapable to properly quantify dynamics at short source-detector distances due to the strong influence of the static component. To solve this problem, we introduce a novel model, which allows recovering the autocorrelation decay of the dynamic part properly. We then apply this novel approach in humans in vivo. We recovered the blood flow index of the leg muscle covered by the thin static turbid layer during the cuff occlusion challenge.
We present results of clinical studies in patients during increase in intra-abdominal pressure (IAP). Changes in brain hemoglobin concentration assessed from time-resolved nearinfrared spectroscopy system were analyzed in frequency domain. The amplitude of power spectral density in respiratory band increases while IAP increases what is related to reduced venous outflow.
We apply time-domain diffuse correlation spectroscopy (TD DCS) to quantify dynamics in a two-layer turbid phantom, where the top layer contains purely static, while bottom layer contains only dynamic scatterers. We demonstrate that the standard TD DCS processing is incapable to properly quantify dynamics at short sourcedetector distances (<1 cm) due to strong influence of the static layer. To solve this problem we introduce a novel model accompanied by the numerical noise-correction, which allows to properly recover the autocorrelation decay of the dynamic homogeneous medium hidden by the static turbid layer. Our approach can be thus beneficial for DCS applications in samples with mixed dynamics.
Transcranial direct current stimulation (tDCS) is currently being used for research and treatment of some neurological and neuropsychiatric disorders, as well as for improvement of cognitive functions. In order to better understand cerebral response to the stimulation and to redefine protocols and dosage, its effects must be monitored. To this end, we have used functional diffuse correlation spectroscopy (fDCS) and time-resolved functional near-infrared spectroscopy (TR-fNIRS) together with electroencephalography (EEG) during and after stimulation of the frontal cortex. Twenty subjects participated in two sessions of stimulation with two different polarity montages and twelve also underwent a sham session. Cerebral blood flow and oxyhemoglobin concentration increased during and after active stimulation in the region under the stimulation electrode while deoxyhemoglobin concentration decreased. The EEG spectrum displayed statistically significant power changes across different stimulation sessions in delta (2 to 4 Hz), theta (4 to 8 Hz), and beta (12 to 18 Hz) bands. Results suggest that fDCS and TR-fNIRS can be employed as neuromonitors of the effects of transcranial electrical stimulation and can be used together with EEG.
The nEUROPt protocol is one of two new protocols developed within the European project nEUROPt to characterize the performances of time-domain systems for optical imaging of the brain. It was applied in joint measurement campaigns to compare the various instruments and to assess the impact of technical improvements. This protocol addresses the characteristic of optical brain imaging to detect, localize, and quantify absorption changes in the brain. It was implemented with two types of inhomogeneous liquid phantoms based on Intralipid and India ink with well-defined optical properties. First, small black inclusions were used to mimic localized changes of the absorption coefficient. The position of the inclusions was varied in depth and lateral direction to investigate contrast and spatial resolution. Second, two-layered liquid phantoms with variable absorption coefficients were employed to study the quantification of layer-wide changes and, in particular, to determine depth selectivity, i.e., the ratio of sensitivities for deep and superficial absorption changes. We introduce the tests of the nEUROPt protocol and present examples of results obtained with different instruments and methods of data analysis. This protocol could be a useful step toward performance tests for future standards in diffuse optical imaging.
Performance assessment of instruments devised for clinical applications is of key importance for validation and quality assurance. Two new protocols were developed and applied to facilitate the design and optimization of instruments for time-domain optical brain imaging within the European project nEUROPt. Here, we present the “Basic Instrumental Performance” protocol for direct measurement of relevant characteristics. Two tests are discussed in detail. First, the responsivity of the detection system is a measure of the overall efficiency to detect light emerging from tissue. For the related test, dedicated solid slab phantoms were developed and quantitatively spectrally characterized to provide sources of known radiance with nearly Lambertian angular characteristics. The responsivity of four time-domain optical brain imagers was found to be of the order of 0.1 m2 sr. The relevance of the responsivity measure is demonstrated by simulations of diffuse reflectance as a function of source-detector separation and optical properties. Second, the temporal instrument response function (IRF) is a critically important factor in determining the performance of time-domain systems. Measurements of the IRF for various instruments were combined with simulations to illustrate the impact of the width and shape of the IRF on contrast for a deep absorption change mimicking brain activation.
Novel protocols were developed and applied in the European project “nEUROPt” to assess and compare the performance
of instruments for time-domain optical brain imaging and of related methods of data analysis. The objective of the first
protocol, “Basic Instrumental Performance”, was to record relevant basic instrumental characteristics in a direct way.
The present paper focuses on the second novel protocol (“nEUROPt” protocol) that was devoted to the assessment of
sensitivity, spatial resolution and quantification of absorption changes within inhomogeneous media. It was implemented
with liquid phantoms based on Intralipid and ink, with black inclusions and, alternatively, in two-layered geometry.
Small black cylinders of various sizes were used to mimic small localized changes of the absorption coefficient. Their
position was varied in depth and lateral direction to address contrast and spatial resolution. Two-layered liquid phantoms
were used, in particular, to determine depth selectivity, i.e. the ratio of contrasts due to a deep and a superficial
absorption change of the same magnitude. We introduce the tests of the “nEUROPt” protocol and present exemplary
results obtained with various instruments. The results are related to measurements with both types of phantoms and to
the analysis of measured time-resolved reflectance based on time windows and moments. Results are compared for the
different instruments or instrumental configurations as well as for the methods of data analysis. The nEUROPt protocol
is also applicable to cw or frequency-domain instruments and could be useful for designing performance tests in future
standards in diffuse optical imaging.
Optical technique based on diffuse reflectance measurement combined with indocyanine green (ICG) bolus tracking is extensively tested as a method for clinical assessment of brain perfusion in adults at the bedside. Methodology of multiwavelength and time-resolved detection of fluorescence light excited in the ICG is presented and advantages of measurements at multiple wavelengths are discussed. Measurements were carried out: 1. on a physical homogeneous phantom to study the concentration dependence of the fluorescence signal, 2. on the phantom to simulate the dynamic inflow of ICG at different depths, and 3. in vivo on surface of the human head. Pattern of inflow and washout of ICG in the head of healthy volunteers after intravenous injection of the dye was observed for the first time with time-resolved instrumentation at multiple emission wavelengths. The multiwavelength detection of fluorescence signal confirms that at longer emission wavelengths, probability of reabsorption of the fluorescence light by the dye itself is reduced. Considering different light penetration depths at different wavelengths, and the pronounced reabsorption at longer wavelengths, the time-resolved multiwavelength technique may be useful in signal decomposition, leading to evaluation of extra- and intracerebral components of the measured signals.
Recent studies have shown that time-resolved optical measurements of the head can estimate changes in the absorption coefficient with depth discrimination. Thus, changes in tissue oxygenation, which are specific to intracranial tissues, can be assessed using this advanced technique, and this method allows us to avoid the influence of changes to extracerebral tissue oxygenation on the measured signals. We report the results of time-resolved optical imaging that was carried out during carotid endarterectomy. This surgery remains the "gold standard" treatment for carotid stenosis, and intraoperative brain oxygenation monitoring may improve the safety of this procedure. A time-resolved optical imager was utilized within the operating theater. This instrument allows for the simultaneous acquisition of 32 distributions of the time-of-flight of photons at two wavelengths on both hemispheres. Analysis of the statistical moments of the measured distributions of the time-of-flight of photons was applied for estimating changes in the absorption coefficient as a function of depth. Time courses of changes in oxy- and deoxyhemoglobin of the extra- and intracerebral compartments during cross-clamping of the carotid arteries were obtained. A decrease in the oxyhemoglobin concentration and an increase in the deoxyhemoglobin concentrations were observed in a large area of the head. Large changes were observed in the hemisphere ipsilateral to the site of clamped carotid arteries. Smaller amplitude changes were noted at the contralateral site. We also found that changes in the hemoglobin signals, as estimated from intracerebral tissue, are very sensitive to clamping of the internal carotid artery, whereas its sensitivity to clamping of the external carotid artery is limited. We concluded that intraoperative multichannel measurements allow for imaging of brain tissue hemodynamics. However, when monitoring the brain during carotid surgery, a single-channel measurement may be sufficient.
Recently, it was shown in measurements carried out on humans that time-resolved near-infrared reflectometry and fluorescence spectroscopy may allow for discrimination of information originating directly from the brain avoiding influence of contaminating signals related to the perfusion of extracerebral tissues. We report on continuation of these studies, showing that the near-infrared light can be detected noninvasively on the surface of the tissue at large interoptode distance. A multichannel time-resolved optical monitoring system was constructed for measurements of diffuse reflectance in optically turbid medium at very large source-detector separation up to 9 cm. The instrument was applied during intravenous injection of indocyanine green and the distributions of times of flight of photons were successfully acquired showing inflow and washout of the dye in the tissue. Time courses of the statistical moments of distributions of times of flight of photons are presented and compared to the results obtained simultaneously at shorter source-detector separations (3, 4, and 5 cm). We show in a series of experiments carried out on physical phantom and healthy volunteers that the time-resolved data acquisition in combination with very large source-detector separation may allow one to improve depth selectivity of perfusion assessment in the brain.
An imaging system for brain oxygenation based on a time-gated, intensified charge-coupled device camera was developed. It allows one to image diffusely reflected light from an investigated medium at defined time windows delayed with respect to the laser pulse. Applying a fast optomechanical switch to deliver the light at a wavelength of 780 nm to nine source fibers allowed one to acquire images in times as short as 4 s. Thus, the system can be applied in in vivo studies. The system was validated in phantom experiments, in which absorbing inclusions were localized at different depths and different lateral positions. Then, the decrease in absorption of the brain tissue related to increase in oxygenation was visualized in the motor cortex area during finger tapping by a healthy volunteer.
A time-resolved optical instrument allowing for noninvasive assessment of cerebral oxygenation is presented. The instrument is equipped with picosecond diode lasers, fast photodetectors, and time-correlated single photon counting electronics. This technology enables depth-resolved estimation of changes in absorption and, in consequence, assessment of changes in hemoglobin concentrations in the brain cortex. Changes in oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb) can be evaluated selectively in extra- and intracerebral tissue compartments using the moments of distributions of times of flight of photons measured at two wavelengths in the near-infrared region. The combination of the data acquired from multiple sources and detectors located on the surface of the head with the depth-resolved analysis, based on the moments, enables imaging of cortex oxygenation. Results of the tests on physical phantoms as well as in vivo validation of the instrument during the motor stimulation experiment are presented.
We present a multi-dimensional TCSPC technique that simultaneously records the photon distribution over the time in the
fluorescence decay, the wavelength, and the coordinates of a two-dimensional scan or the time since the start of the experiment.
We demonstrate the application of the technique to diffuse optical tomography, single-point autofluorescence measurements
of skin, and multi-spectra autofluorescence lifetime imaging of tissue.
The laser Doppler method offers a non-invasive, real time technique for monitoring of blood perfusion in microcirculation. In practical measurements the perfusion index is given only in relative values. Thus, accurate and reproducible results can be only obtained when using a well controlled stimulation test. The aim of this study was evaluation of the thermal stimulation test, which is frequently used to investigate microcirculation in patients with Raynaud's syndrome. Three types of thermal tests, in which air or water with temperature in range 5°C - 40°C were used. Ten normal volunteers and fifteen patients with clinical symptoms of the primary Raynaud's syndrome were enrolled in this study. To estimate skin microcirculation changes during the thermal test, the multichannel laser Doppler system and laser Doppler scanner were used. The obtained results were analyzed from the point of view of the efficiency of these methods and the thermal provocative tests in differentiation of normal subjects and patient with Raynaud's syndrome.
Time-resolved optical measurements allow for evaluation of optical properties of the tissue (in particular, absorption and reduced scattering coefficient). A four-channel time-resolved spectroscopic system for measurements of the tissue optical properties is presented. Four semiconductor diode lasers were used for emission of picosecond pulses at wavelengths of 633, 687, 784 and 832 nm. Optical fibers were applied to deliver the laser light into the tissue studied. The diffusely reflected light was transmitted to the photodetectors through fiber bundles. Four photomultiplier tubes were used for light detection and four independent time-correlated single photon counting boards were applied to obtain distributions of times of flight of photons. Measurements on liquid phantoms were carried out to test the temporal resolution and stability of the system and to demonstrate its usefulness in non-invasive determination of optical properties of the tissue.
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