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Near-infrared spectroscopy is a noninvasive optical method used primarily to monitor tissue oxygenation due to the absorption properties of hemoglobin. Accurate estimation of hemoglobin concentrations and other light absorbers requires techniques that can separate the effect of absorption from the much greater effect of light scattering. One of the most advanced methods is time-resolved near-infrared spectroscopy (TR-NIRS), which measures the absorption and scattering coefficients of a turbid medium by modeling the recorded distribution time of flight of photons. A challenge with TR-NIRS is that it requires accurate characterization of the dispersion caused by the system. In this study, we present a method for circumventing this problem by applying statistical moment analysis to two time-of-flight distributions measured at separated source-detector distances. Simulations based on analytical models and Monte Carlo code, and tissue-mimicking phantoms, were used to demonstrate its accuracy for source-detector distances typically used in neuroimaging applications. The simplicity of the approach is well suited to real-time applications requiring accurate quantification of the optical properties of a turbid medium.
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Nefelometria e Turbidimetria/métodos , Fenômenos Ópticos , Algoritmos , Método de Monte Carlo , Imagens de Fantasmas , Fótons , Espectroscopia de Luz Próxima ao Infravermelho , Fatores de TempoRESUMO
BACKGROUND: It is believed that endothelial dysfunction may be a link between systemic and ocular dysregulation in glaucoma. The aim of this study was to evaluate peripheral vascular reactive hyperemia in response to occlusion test and to correlate peripheral vascular findings with retrobulbar hemodynamics parameters in patients with normal-tension glaucoma. MATERIAL AND METHODS: Forty-eight patients with normal-tension glaucoma (mean age 58.1 years, 38 women) and 40 control subjects (mean age 54.1 years, 36 women) were subjected to a brachial arterial occlusion test and color Doppler imaging (LOGIQ 9, GE Medical Systems) of the retrobulbar arteries. Finger hyperemia was assessed by using a 2-channel laser Doppler flowmeter (MBF-3D, Moor Instruments, Ltd.). Time parameters (time to peak flow, half-time of hyperemia, time of recovery) and amplitude parameters (maximum hyperemia response, biological zero) of the post-occlusive reactive hyperemia signal pattern as well as velocities and resistance index of the ophthalmic, central retinal, and short posterior ciliary arteries were evaluated and compared between study groups. RESULTS: In glaucoma patients, time to peak flow and half-time of hyperemia were significantly longer (21.4 vs. 12.0 s, p=0.02 and 74.1 vs. 44.2 s, p=0.03, respectively) and biological zero was significantly lower (2.4 vs. 3.2, p=0.01) comparing with healthy subjects. In glaucoma patients, peak-systolic and end-diastolic velocities of central retinal artery were significantly lower (12.8 vs.14.1, p=0.03 and 3.9 vs. 4.7, p=0.01, respectively) and resistance index of this artery was significantly higher (0.69 vs. 0.67, p=0.03) compared to controls. In the glaucoma group, maximum hyperemic response was negatively correlated with the resistance index of temporal short posterior ciliary arteries (r=-0.4, p=0.01), whereas in the control group half-time of hyperemia was negatively correlated with end-diastolic velocity of the central retinal artery (r=-0.3, p=0.03). CONCLUSIONS: Arterial occlusion test elicited a prolonged systemic hyperemia response in patients with glaucoma as compared with healthy subjects. Retrobulbar blood flow alterations in glaucoma patients may be related to systemic vascular dysregulation.
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Glaucoma/complicações , Hiperemia/etiologia , Feminino , Glaucoma/diagnóstico por imagem , Glaucoma/fisiopatologia , Hemodinâmica , Humanos , Hiperemia/diagnóstico por imagem , Hiperemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Ultrassonografia Doppler em CoresRESUMO
Time-domain diffuse correlation spectroscopy (td-DCS) enables the depth discrimination in tissue's blood flow recovery, considering the fraction of photons detected with higher time of flight (TOF) and longer pathlength through the tissue. However, the recovery result depends on factors such as the instrument response function (IRF), analyzed TOF gate start time, gate width and the source-detector separation (SDS). In this research we evaluate the performance of the td-DCS technique at three SDSs of 1.5, 2 and 2.5â cm to recover cerebral blood flow (CBF). To do that we presented comprehensive characterization of the td-DCS system through a series of phantom experiments. First by quality metrices such as coefficient of variation and contrast-to-noise ratios, we identified optimal time gate(s) of the TOF to extract dynamics of particles. Then using sensitivity metrices, each SDS ability to detect dynamics of particles in superficial and deeper layer was evaluated. Finally, td-DCS at each SDS was tested on healthy volunteers during cuff occlusion test and breathing tasks. According to phantom measurements, the sensitivity to estimate perfusion within the deep layer located at depth of 1.5â cm from the surface can be increased more than two times when the SDS increases from 1.5â cm to 2.5â cm.
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Near-infrared spectroscopy (NIRS) is an established technique for measuring tissue oxygen saturation (StO2), which is of high clinical value. For tissues that have layered structures, it is challenging but clinically relevant to obtain StO2 of the different layers, e.g. brain and scalp. For this aim, we present a new method of data analysis for time-domain NIRS (TD-NIRS) and a new two-layered blood-lipid phantom. The new analysis method enables accurate determination of even large changes of the absorption coefficient (Δµa) in multiple layers. By adding Δµa to the baseline µa, this method provides absolute µa and hence StO2 in multiple layers. The method utilizes (i) changes in statistical moments of the distributions of times of flight of photons (DTOFs), (ii) an analytical solution of the diffusion equation for an N-layered medium, (iii) and the Levenberg-Marquardt algorithm (LMA) to determine Δµa in multiple layers from the changes in moments. The method is suitable for NIRS tissue oximetry (relying on µa) as well as functional NIRS (fNIRS) applications (relying on Δµa). Experiments were conducted on a new phantom, which enabled us to simulate dynamic StO2 changes in two layers for the first time. Two separate compartments, which mimic superficial and deep layers, hold blood-lipid mixtures that can be deoxygenated (using yeast) and oxygenated (by bubbling oxygen) independently. Simultaneous NIRS measurements can be performed on the two-layered medium (variable superficial layer thickness, L), the deep (homogeneous), and/or the superficial (homogeneous). In two experiments involving ink, we increased the nominal µa in one of two compartments from 0.05 to 0.25â cm-1, L set to 14.5 mm. In three experiments involving blood (L set to 12, 15, or 17 mm), we used a protocol consisting of six deoxygenation cycles. A state-of-the-art multi-wavelength TD-NIRS system measured simultaneously on the two-layered medium, as well as on the deep compartment for a reference. The new method accurately determined µa (and hence StO2) in both compartments. The method is a significant progress in overcoming the contamination from the superficial layer, which is beneficial for NIRS and fNIRS applications, and may improve the determination of StO2 in the brain from measurements on the head. The advanced phantom may assist in the ongoing effort towards more realistic standardized performance tests in NIRS tissue oximetry. Data and MATLAB codes used in this study were made publicly available.
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Research on the spatial distribution of sensitivity of time-domain near infrared diffuse reflectance measurement is reported in this paper. The main objective of the investigation is to validate theoretically calculated sensitivity profiles for a measurement geometry with two detectors and two sources in which sensitivity profiles of statistical moments of distributions of time of flight of photons (DTOFs) are spatially restricted to a region underneath the detectors. For this dual subtraction method, smaller sensitivities to changes appearing in the superficial layer of the medium were observed compared to the single distance and single subtraction methods. Experimental validation of this approach is based on evaluation of changes in the statistical moments of DTOFs measured on a liquid phantom with local absorption perturbations. The spatial distributions of sensitivities, depth-related sensitivity and depth selectivities were obtained from the dual subtraction method and compared with those from single distance and single subtraction approaches. Also, the contrast to noise ratio (CNR) was calculated for the dual subtraction technique and combined with depth selectivity in order to assess the overall performance (product of CNR and depth selectivity) of the method. Spatial sensitivity profiles from phantom experiments are in a good agreement with the results of theoretical studies and feature more locally restricted sensitivity volume with the point of maximal sensitivity located deeper. The highest value of overall performance was obtained experimentally for the second statistical moment in the dual subtraction method (â¼10.8) surpassing that of the single distance method (â¼8.7). This confirms the advantage of dual subtraction measurement geometries in the suppression of optical signals originated in the superficial layer of the medium.
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Here we show a method of the lock-in amplifying near-infrared signals originating within a human brain. It implies using two 90-degree rotated source-detector pairs fixed on a head surface. Both pairs have a joint sensitivity region located towards the brain. A direct application of the lock-in technique on both signals results in amplifying common frequency components, e.g. related to brain cortex stimulation and attenuating the rest, including all components not related to the stimulation: e.g. pulse, instrumental and biological noise or movement artefacts. This is a self-driven method as no prior assumptions are needed and the noise model is provided by the interfering signals themselves. We show the theory (classical modified Beer-Lambert law and diffuse optical tomography approaches), the algorithm implementation and tests on a finite element mathematical model and in-vivo on healthy volunteers during visual cortex stimulation. The proposed hardware and algorithm complexity suit the entire spectrum of (continuous wave, frequency domain, time-resolved) near-infrared spectroscopy systems featuring real-time, direct, robust and low-noise brain activity registration tool. As such, this can be of special interest in optical brain computer interfaces and high reliability/stability monitors of tissue oxygenation.
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The COVID-19 pandemic outbreak led to a global ventilator shortage. Hence, various strategies for using a single ventilator to support multiple patients have been considered. A device called Ventil previously validated for independent lung ventilation was used in this study to evaluate its usability for shared ventilation. We performed experiments with a total number of 16 animals. Eight pairs of pigs were ventilated by a ventilator or anesthetic machine and by Ventil for up to 27 h. In one experiment, 200 ml of saline was introduced to one subject's lungs to reduce their compliance. The experiments were analyzed in terms of arterial blood gases and respiratory parameters. In addition to the animal study, we performed a series of laboratory experiments with artificial lungs (ALs). The resistance and compliance of one AL (affected) were altered, while the tidal volume (TV) and peak pressure (Ppeak) in the second (unaffected) AL were analyzed. In addition, to assess the risk of transmission of pathogens between AL respiratory tracts, laboratory tests were performed using phantoms of virus particles. The physiological level of analyzed parameters in ventilated animals was maintained, except for CO2 tension, for which a permissive hypercapnia was indicated. Experiments did not lead to injuries in the animal's lungs except for one subject, as indicated by CT scan analysis. In laboratory experiments, changes in TV and Ppeak in the unaffected AL were less than 11%, except for 2 cases where the TV change was 20%. No cross-contamination was found in simulations of pathogen transmission. We conclude that ventilation using Ventil can be considered safe in patients undergoing deep sedation without spontaneous breathing efforts.
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COVID-19 , Pandemias , Animais , Humanos , Suínos , Ventiladores Mecânicos , Pulmão/diagnóstico por imagem , Respiração Artificial , Animais de Laboratório , Modelos AnimaisRESUMO
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.
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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.
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Laboratórios , Óptica e Fotônica , Imagens de Fantasmas , Reprodutibilidade dos Testes , Análise EspectralRESUMO
Monitoring of human tissue hemodynamics is invaluable in clinics as the proper blood flow regulates cellular-level metabolism. Time-domain diffuse correlation spectroscopy (TD-DCS) enables noninvasive blood flow measurements by analyzing temporal intensity fluctuations of the scattered light. With time-of-flight (TOF) resolution, TD-DCS should decompose the blood flow at different sample depths. For example, in the human head, it allows us to distinguish blood flows in the scalp, skull, or cortex. However, the tissues are typically polydisperse. So photons with a similar TOF can be scattered from structures that move at different speeds. Here, we introduce a novel approach that takes this problem into account and allows us to quantify the TOF-resolved blood flow of human tissue accurately. We apply this approach to monitor the blood flow index in the human forearm in vivo during the cuff occlusion challenge. We detect depth-dependent reactive hyperemia. Finally, we applied a controllable pressure to the human forehead in vivo to demonstrate that our approach can separate superficial from the deep blood flow. Our results can be beneficial for neuroimaging sensing applications that require short interoptode separation.
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Fluxo Sanguíneo Regional , Análise Espectral/métodos , Testa/irrigação sanguínea , Humanos , Imagens de FantasmasRESUMO
Time-domain diffuse correlation spectroscopy (TD-DCS) is an emerging optical technique that enables noninvasive measurement of microvascular blood flow with photon path-length resolution. In TD-DCS, a picosecond pulsed laser with a long coherence length, adequate illumination power, and narrow instrument response function (IRF) is required, and satisfying all these features is challenging. To this purpose, in this study we characterized the performance of three different laser sources for TD-DCS. First, the sources were evaluated based on their emission spectrum and IRF. Then, we compared the signal-to-noise ratio and the sensitivity to velocity changes of scattering particles in a series of phantom measurements. We also compared the results for in vivo measurements, performing an arterial occlusion protocol on the forearm of three adult subjects. Overall, each laser has the potential to be successfully used both for laboratory and clinical applications. However, we found that the effects caused by the IRF are more significant than the effect of a limited temporal coherence.
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We present and validate a multi-wavelength time-domain near-infrared spectroscopy (TD-NIRS) system that avoids switching wavelengths and instead exploits the full capability of a supercontinuum light source by emitting and acquiring signals for the whole chosen range of wavelengths. The system was designed for muscle and brain oxygenation monitoring in a clinical environment. A pulsed supercontinuum laser emits broadband light and each of two detection modules acquires the distributions of times of flight of photons (DTOFs) for 16 spectral channels (used width 12.5â nm / channel), providing a total of 32 DTOFs at up to 3â Hz. Two emitting fibers and two detection fiber bundles allow simultaneous measurements at two positions on the tissue or at two source-detector separations. Three established protocols (BIP, MEDPHOT, and nEUROPt) were used to quantitatively assess the system's performance, including linearity, coupling, accuracy, and depth sensitivity. Measurements were performed on 32 homogeneous phantoms and two inhomogeneous phantoms (solid and liquid). Furthermore, measurements on two blood-lipid phantoms with a varied amount of blood and Intralipid provide the strongest validation for accurate tissue oximetry. The retrieved hemoglobin concentrations and oxygen saturation match well with the reference values that were obtained using a commercially available NIRS system (OxiplexTS) and a blood gas analyzer (ABL90 FLEX), except a discrepancy occurs for the lowest amount of Intralipid. In-vivo measurements on the forearm of three healthy volunteers during arterial (250 mmHg) and venous (60 mmHg) cuff occlusions provide an example of tissue monitoring during the expected hemodynamic changes that follow previously well-described physiologies. All results, including quantitative parameters, can be compared to other systems that report similar tests. Overall, the presented TD-NIRS system has an exemplary performance evaluated with state-of-the-art performance assessment methods.
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Near-infrared spectroscopy (NIRS) of the human brain is aiming at the non-invasive determination of concentration changes of oxy- and deoxyhemoglobin in the cortex. However, it usually relies on the assumption of spatially homogeneous absorption changes. To overcome this limitation we performed instrumental and methodological developments of time-resolved NIRS with the aim to achieve depth resolution. We present our recently developed time-domain near-infrared brain imager based on picosecond diode lasers and time-correlated single photon counting (TCSPC) which can be used at the bedside. To achieve depth localization of absorption changes we analysed statistical moments (integral, mean time of flight and variance) of measured time-of-flight distributions of diffusely reflected photons. In particular, variance has a selective sensitivity to deep absorptions changes and provides a suitable representation of cerebral signals. The separation of cerebral and extracerebral changes of hemoglobin concentrations is demonstrated for a motor stimulation experiment.
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Mapeamento Encefálico/métodos , Imageamento Tridimensional/métodos , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Adulto , Humanos , Fenômenos Ópticos , Estimulação Física , Fatores de TempoRESUMO
Time-domain measurements facilitate the elimination of the influence of extracerebral, systemic effects, a key problem in functional near-infrared spectroscopy (fNIRS) of the adult human brain. The analysis of measured time-of-flight distributions of photons often relies on moments or time windows. However, a systematic and quantitative characterization of the performance of these measurands is still lacking. Based on perturbation simulations for small localized absorption changes, we compared spatial sensitivity profiles and depth selectivity for moments (integral, mean time of flight and variance), photon counts in time windows and their ratios for different time windows. The influence of the instrument response function (IRF) was investigated for all measurands and for various source-detector separations. Variance exhibits the highest depth selectivity among the moments. Ratios of photon counts in different late time windows can achieve even higher selectivity. An advantage of moments is their robustness against the shape of the IRF and instrumental drifts.
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Time-domain optical brain imaging techniques introduce a number of different measurands for analyzing absorption changes located deep in the tissue, complicated by superficial absorption changes and noise. We implement a method that allows analysis, quantitative comparison and performance ranking of measurands under various conditions - including different values of reduced scattering coefficient, thickness of the superficial layer, and source-detector separation. Liquid phantom measurements and Monte Carlo simulations were carried out in two-layered geometry to acquire distributions of times of flight of photons and to calculate the total photon count, mean time of flight, variance, photon counts in time windows and ratios of photon counts in different time windows. Quantitative comparison of performance was based on objective metrics: relative contrast, contrast-to-noise ratio (CNR) and depth selectivity. Moreover, the product of CNR and depth selectivity was used to rank the overall performance and to determine the optimal source-detector separation for each measurand. Variance ranks the highest under all considered conditions.
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A methodology for the assessment of the cerebral hemodynamic reaction to normotensive hypovolemia, reduction in cerebral perfusion and orthostatic stress leading to ischemic hypoxia and reduced muscular tension is presented. Most frequently, the pilots of highly maneuverable aircraft are exposed to these phenomena. Studies were carried out using the system consisting of a chamber that generates low pressure around the lower part of the body - LBNP (lower body negative pressure) placed on the tilt table. An in-house developed 6-channel NIRS system operating at 735 and 850 nm was used in order to assess the oxygenation of the cerebral cortex, based on measurements of diffusely reflected light in reflectance geometry. The measurements were carried out on a group of 12 active pilots and cadets of the Polish Air Force Academy and 12 healthy volunteers. The dynamics of changes in cerebral oxygenation was evaluated as a response to LBNP stimuli with a simultaneous rapid change of the tilt table angle. Parameters based on calculated changes of total hemoglobin concentration were proposed allowing to evaluate differences in reactions observed in control subjects and pilots/cadets. The results of orthogonal partial least squares-discriminant analysis based on these parameters show that the subjects can be classified into their groups with 100% accuracy.
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We have studied the spatial distributions of the sensitivity of time-resolved near-infrared diffuse reflectance measurement. Sensitivity factors representing a change of parameters of a measured optical signal induced by absorption perturbation in a certain voxel of the medium were simulated using the diffusion equation solution. The parameters were statistical moments of measured distributions of time of flight of photons (DTOFs) i.e., the total number of photons, mean time of flight and variance. The distributions of the sensitivity of statistical moments of DTOFs to a change in absorption were generated for various source-detector separations and various optical properties of the medium. Furthermore, differential sensitivity distributions for two different source-detector separations were calculated. A measurement geometry, in which two detection spots, separated by 5 mm, in combination with two sources was proposed. For this setup differences between the signals obtained for both detectors were calculated independently for both sources and afterward summed up for both source positions. Obtained differences in moments of DTOFs assessed at two source-detector separations and summed up for different positioning of the sources allowed to shape up the sensitivity profiles. Calculated sensitivity profiles show that positive sensitivities of the mean time of flight of photons and variance of the DTOF can be obtained. These positive sensitivity areas are located just between both detection spots and cover the compartment located deeply in the medium. The sensitivity in superficial compartments of the medium is negative and much smaller in amplitude. The proposed technique can be used for improved discrimination of optical signals related to the intracerebral change in absorption which remains a serious obstacle in the application of the NIRS technique in the assessment of brain oxygenation or perfusion.
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In this paper, we propose the application of time-domain near-infrared spectroscopy to the assessment of oscillations in cerebral hemodynamics. These oscillations were observed in the statistical moments of the distributions of time of flight of photons (DTOFs) measured on the head. We analyzed the zeroth and second centralized moments of DTOFs (total number of photons and variance) to obtain their spectra to provide parameters for the frequency components of microcirculation, which differ between the extracerebral and intracerebral layers of the head. Analysis of these moments revealed statistically significant differences between a control group of healthy subjects and a group of patients with severe neurovascular disorders, which is a promising result for the assessment of cerebral microcirculation and cerebral autoregulation mechanisms.
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Time-resolved near-infrared spectroscopy (TR-NIRS) measurements can be used to recover changes in concentrations of tissue constituents ( Δ C ) by applying the moments method and the Beer-Lambert law. In this work we carried out the error propagation analysis allowing to calculate the standard deviations of uncertainty in estimation of the Δ C . Here, we show the process of choosing wavelengths for the evaluation of hemodynamic (oxy-, deoxyhemoglobin) and metabolic (cytochrome-c-oxidase (CCO)) responses within the brain tissue as measured with an in-house developed TR-NIRS multi-wavelength system, which measures at 16 consecutive wavelengths separated by 12.5â nm and placed between 650 and 950â nm. Data generated with Monte Carlo simulations on three-layered model (scalp, skull, brain) for wavelengths range from 650 to 950â nm were used to carry out the error propagation analysis for varying choices of wavelengths. For a detector with a spectrally uniform responsivity, the minimal standard deviation of the estimated changes in CCO within the brain layer, σ Δ C CCO brain = 0.40 µM, was observed for the 16 consecutive wavelengths from 725 to 912.5â nm. For realistic a detector model, i.e. the spectral responsivity characteristic is considered, the minimum, σ Δ C CCO brain = 0.47 µM, was observed at the 16 consecutive wavelengths from 688 to 875â nm. We introduce the method of applying the error propagation analysis to data as measured with spectral TR-NIRS systems to calculate uncertainty of recovery of tissue constituents concentrations.
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An intra-abdominal pressure (IAP) is correlated with cerebral perfusion, in a mechanism of reducing venous outflow. The elevated intra-abdominal pressure leads to an increase in the intracranial pressure and a decrease in the cerebral perfusion pressure. We studied the relationship between the IAP and the cerebral oxygenation with the use of the near infrared spectroscopy technique during a gynecological surgery. The changes in hemoglobin concentrations were analyzed in the time-frequency domain in the frequency band related to respiration. The measurements were carried out in 15 subjects who underwent laparoscopic surgery. During the laparoscopy, the intra-abdominal cavity was insufflated with CO2, which caused a controlled increase in the IAP. It was observed that the amplitudes of respiration-related waves present in hemoglobin concentration signals show an increase of 1.5 to 8.5 times during elevation of the IAP by 15 mmHg.