Exclusive detection of cerebral hemodynamics in functional near-infrared spectroscopy by reflectance modulation of the scalp surface.

SIGNIFICANCE: Functional near-infrared spectroscopy (fNIRS) is a technique for detecting regional hemodynamic responses associated with neural activation in the cerebral cortex. The absorption changes due to hemodynamic changes in the scalp cause considerable signal contamination in the fNIRS measurement. A method for extracting hemodynamic changes in the cerebral tissue is required for reliable fNIRS measurement. AIM: To exclusively detect cerebral functional hemodynamic changes, we developed an fNIRS technique using reflectance modulation of the scalp surface. APPROACH: The theoretical feasibility of the proposed method was proven by a simulation calculation of light propagation. Its practical feasibility was evaluated by a phantom experiment and brain activation simulation mimicking human fNIRS experiments. RESULTS: The simulation calculation revealed that the partial path length of the scalp was changed by reflectance modulation of the scalp surface. The influence of absorption change in the superficial layer was successfully reduced by the proposed method, using only measurement data, in the phantom experiment. The proposed method was applicable to human experiments of standard designs, achieving statistical significance within an acceptable experimental time-frame. CONCLUSIONS: Removal of the scalp hemodynamic effect by the proposed technique will increase the quality of fNIRS data, particularly in measurements in neonates and infants that typically would require a dense optode arrangement.

In situ estimation of optical properties of rat and monkey brains using femtosecond time-resolved measurements.

An accurate knowledge of tissue optical properties (absorption coefficients, µa, and reduced scattering coefficients, µs') is critical for precise modeling of light propagation in biological tissue, essential for developing diagnostic and therapeutic optical techniques that utilize diffusive photons. A great number of studies have explored the optical properties of various tissue, and these values are not known in detail due to difficulties in the experimental determination and significant variations in tissue constitution. Especially, in situ estimates of the optical properties of brain tissue, a common measurement target in optical imaging, is a challenge because of its layer structure (where the thin gray matter covers the white matter). Here, we report an approach to in situ estimates of the µa and µs' of the gray and white matter in living rat and monkey brains by using femtosecond time-resolved measurements and Monte Carlo simulation. The results demonstrate that the µa of the gray matter is larger than that of the white matter, while there was no significant difference in the µs' between the gray and white matter. The optical properties of the rat brain were very similar to those of the monkey brain except for the µa of the gray matter here.

Quantitative evaluation of deep and shallow tissue layers' contribution to fNIRS signal using multi-distance optodes and independent component analysis.

To quantify the effect of absorption changes in the deep tissue (cerebral) and shallow tissue (scalp, skin) layers on functional near-infrared spectroscopy (fNIRS) signals, a method using multi-distance (MD) optodes and independent component analysis (ICA), referred to as the MD-ICA method, is proposed. In previous studies, when the signal from the shallow tissue layer (shallow signal) needs to be eliminated, it was often assumed that the shallow signal had no correlation with the signal from the deep tissue layer (deep signal). In this study, no relationship between the waveforms of deep and shallow signals is assumed, and instead, it is assumed that both signals are linear combinations of multiple signal sources, which allows the inclusion of a "shared component" (such as systemic signals) that is contained in both layers. The method also assumes that the partial optical path length of the shallow layer does not change, whereas that of the deep layer linearly increases along with the increase of the source-detector (S-D) distance. Deep- and shallow-layer contribution ratios of each independent component (IC) are calculated using the dependence of the weight of each IC on the S-D distance. Reconstruction of deep- and shallow-layer signals are performed by the sum of ICs weighted by the deep and shallow contribution ratio. Experimental validation of the principle of this technique was conducted using a dynamic phantom with two absorbing layers. Results showed that our method is effective for evaluating deep-layer contributions even if there are high correlations between deep and shallow signals. Next, we applied the method to fNIRS signals obtained on a human head with 5-, 15-, and 30-mm S-D distances during a verbal fluency task, a verbal working memory task (prefrontal area), a finger tapping task (motor area), and a tetrametric visual checker-board task (occipital area) and then estimated the deep-layer contribution ratio. To evaluate the signal separation performance of our method, we used the correlation coefficients of a laser-Doppler flowmetry (LDF) signal and a nearest 5-mm S-D distance channel signal with the shallow signal. We demonstrated that the shallow signals have a higher temporal correlation with the LDF signals and with the 5-mm S-D distance channel than the deep signals. These results show the MD-ICA method can discriminate between deep and shallow signals.

Estimating the absorption coefficient of the bottom layer in four-layered turbid mediums based on the time-domain depth sensitivity of near-infrared light reflectance.

Expanding our previously proposed "time segment analysis" for a two-layered turbid medium, this study attempted to selectively determine the absorption coefficient (µa) of the bottom layer in a four-layered human head model with time-domain near-infrared measurements. The difference curve in the temporal profiles of the light attenuation between an object and a reference medium, which are obtained from Monte Carlo simulations, is divided into segments along the time axis, and a slope for each segment is calculated to obtain the depth-dependent µa(µaseg). The reduced scattering coefficient (µs') of the reference is determined by curve fitting with the temporal point spread function derived from the analytical solution of the diffusion equation to the time-resolved reflectance of the object. The deviation of µaseg from the actual µa is expressed by a function of the ratio of µaseg in an earlier time segment to that in a later segment for mediums with different optical properties and thicknesses of the upper layers. Using this function, it is possible to determine the µa of the bottom layer in a four-layered epoxy resin-based phantom. These results suggest that the method reported here has potential for determining the µa of the cerebral tissue in humans.

Dynamic phantom with two stage-driven absorbers for mimicking hemoglobin changes in superficial and deep tissues.

In near-infrared spectroscopy (NIRS) for monitoring brain activity and cerebral functional connectivity, the effect of superficial tissue on NIRS signals needs to be considered. Although some methods for determining the effect of scalp and brain have been proposed, direct validation of the methods has been difficult because the actual absorption changes cannot be known. In response to this problem, we developed a dynamic phantom that mimics hemoglobin changes in superficial and deep tissues, thus allowing us to experimentally validate the methods. Two absorber layers are independently driven with two one-axis automatic stages. We can use the phantom to design any type of waveform (e.g., brain activity or systemic fluctuation) of absorption change, which can then be reproducibly measured. To determine the effectiveness of the phantom, we used it for a multiple source-detector distance measurement. We also investigated the performance of a subtraction method with a short-distance regressor. The most accurate lower-layer change was obtained when a shortest-distance channel was used. Furthermore, when an independent component analysis was applied to the same data, the extracted components were in good agreement with the actual signals. These results demonstrate that the proposed phantom can be used for evaluating methods of discriminating the effects of superficial tissue.

Reduction of image artifacts induced by change in the optode coupling in time-resolved diffuse optical tomography.

Tomographic images of the optical properties can be reconstructed using inversion algorithms for diffuse optical tomography (DOT); however, changes in the optode coupling that occurs while obtaining an object's measurements may often lead to the presence of artifacts in the reconstructed images. To reduce the number of artifacts induced by optode coupling, previous studies have introduced (unknown) coupling coefficients in reconstruction algorithms, which were found to be effective for continuous wave- and frequency-domain DOT. This study aims to investigate the effects of optode calibration on the reconstructed images of time-domain DOT. Here, coupling coefficients are incorporated into the time-domain DOT algorithm based on a modified generalized pulse spectrum technique. The images of the absorption coefficient are reconstructed in various numerical simulations, phantom experiments, and in vivo experiments of time-domain DOT. As a result, the artifacts resulting from changes in optode coupling are reduced in the reconstructed images of the absorption coefficient, thereby demonstrating that introduction of coupling coefficients is effective in time-domain DOT. Moreover, numerical simulations, phantom experiments, and in vivo studies have validated this algorithm.

Optical scanning system for light-absorption measurement of deep biological tissue.

A noncontact near-infrared scanning system for multi-distance absorption measurement of deep biological tissue was developed. An 808-nm laser, whose focal point on the surface of biological tissue is controlled by a galvano scanner, is used as a light source. A phosphor is placed at a detection focal point on the tissue surface. The light that propagates through tissue and exits from the tissue surface beneath the phosphor excites the phosphor. The fluorescence emitted from the phosphor is detected by an avalanche photodiode. The system is used to measure 20 points on tissue surface at which source-detector (S-D) distances are 7-45 mm (with 2-mm intervals). Neither the light source nor the detector contacts the tissue surface. The system was validated by using it to measure the absorption change of an absorber (which is embedded in a deep layer of a tissue-simulating phantom) while the surface-layer thickness of the phantom was changed from 1 to 12 mm. It was demonstrated that both the relative absorption change of the absorber and the absolute thickness of the surface layer can be estimated from the measured optical-density change (ΔOD) and the dependence of ΔOD on S-D distance, respectively.

Imaging of forearm-muscle activities by CP-MCT and TR-DOT.

Chirp Pulse Microwave Computed Tomography (CP-MCT) has been developed to visualize activities of forearm muscles during exercise. The change in the gray levels between two images obtained before and after loading exercises showed position dependence. This was produced by physiological- or biochemical- changes in forearm muscles caused by grasping a rubber ball in the bolus tank that was filled with saline solution. However, nobody knows the truth how this change was produced. In order to infer the mechanism of the gray level change caused by the exercise, the forearm exercise was investigated also by using electromyography and Time-Resolved Diffuse Optical Tomography (TR-DOT). Measurements by CP-MCT and TR-DOT were not performed simultaneously, but both images obtained under the same experimental condition showed similar changes in each tomogram. They were characterized by activation of inner muscles needed for continuing the exercise.

A self-normalized, full time-resolved method for fluorescence diffuse optical tomography.

A full time-resolved scheme that has been previously applied in diffuse optical tomography is extended to time-domain fluorescence diffuse optical tomography regime, based on a finite-element-finite-time-difference photon diffusion modeling and a Newton-Raphson inversion framework. The merits of using full time-resolved data are twofold: it helps evaluate the intrinsic performance of time-domain mode for improvement of image quality and set up a valuable reference to the assessment of computationally efficient featured-data-based algorithms, and provides a self-normalized implementation to preclude the necessity of the scaling-factor calibration and spectroscopic-feature assessments of the system as well as to overcome the adversity of system instability. We validate the proposed methodology using simulated data, and evaluate its performances of simultaneous recovery of the fluorescent yield and lifetime as well as its superiority to the featured-data one in the fidelity of image reconstruction.

Time-resolved diffuse optical tomography and its application to in vitro and in vivo imaging.

This work reviews our research during the past several years on time-resolved (TR) near-infrared diffuse optical tomography (DOT). Following an introduction of the measuring modes, two proposed schemes of image reconstruction in TR-DOT are described: one utilizes the full TR data, and the other, referred to as the modified generalized pulse spectrum technique (GPST), uses the featured data extracted from the TR measurement. The performances of the two algorithms in quantitativeness and spatial resolution are comparatively investigated with 2-D simulated data. TR-DOT images are then presented for phantom experiments, which are obtained by using a 16-channel time-correlated single photon counting system, and the factors affecting the quantification of the reconstruction are discussed. Finally, in vitro and in vivo imaging examples are illustrated for validating the capibility of TR-DOT to provide not only the anatomical but also the physiological information of the objects.

A linear, featured-data scheme for image reconstruction in time-domain fluorescence molecular tomography.

Fluorescence diffuse optical tomography (DOT) has attracted many attentions from the community of biomedical imaging, since it provides effective enhancement in imaging contrast. This modality is now rapidly evolving as a potential means of monitoring molecular events in small living organisms with help of molecule-specific contrast agents, referred to as fluorescence molecular tomography (FMT). FMT could greatly promote pathogenesis research, drug development, and therapeutic intervention. Although FMT in steady-state and frequency-domain modes have been heavily investigated, the extension to time-domain scheme is imminent for its several unique advantages over the others. By extending the previously developed generalized pulse spectrum technique for time-domain DOT, we propose a linear, featured-data image reconstruction algorithm for time-domain FMT that can simultaneously reconstruct both fluorescent yield and lifetime images of multiple fluorophores, and validate the methodology with simulated data.

Time-resolved diffuse optical tomographic imaging for the provision of both anatomical and functional information about biological tissue.

We present in vivo images of near-infrared (NIR) diffuse optical tomography (DOT) of human lower legs and forearm to validate the dual functions of a time-resolved (TR) NIR DOT in clinical diagnosis, i.e., to provide anatomical and functional information simultaneously. The NIR DOT system is composed of time-correlated single-photon-counting channels, and the image reconstruction algorithm is based on the modified generalized pulsed spectral technique, which effectively incorporates the TR data with reasonable computation time. The reconstructed scattering images of both the lower legs and the forearm revealed their anatomies, in which the bones were clearly distinguished from the muscles. In the absorption images, some of the blood vessels were observable. In the functional imaging, a subject was requested to do handgripping exercise to stimulate physiological changes in the forearm tissue. The images of oxyhemoglobin, deoxyhemoglobin, and total hemoglobin concentration changes in the forearm were obtained from the differential images of the absorption at three wavelengths between the exercise and the rest states, which were reconstructed with a differential imaging scheme. These images showed increases in both blood volume and oxyhemoglobin concentration in the arteries and simultaneously showed hypoxia in the corresponding muscles. All the results have demonstrated the capability of TR NIR DOT by reconstruction of the absolute images of the scattering and the absorption with a high spatial resolution that finally provided both the anatomical and functional information inside bulky biological tissues.

Optical tomographic mapping of cerebral haemodynamics by means of time-domain detection: methodology and phantom validation.

One of the primary applications of diffuse optical imaging is to localize and quantify the changes in the cerebral oxygenation during functional brain activation. Up to now, data from an optical imager are simply presented as a two-dimensional (2D) topographic map using the modified Beer-Lambert law that assumes homogeneous optical properties beneath each optode. Due to the highly heterogeneous nature of the optical properties in the brain, the assumption is evidently invalid, leading to both low spatial resolution and inaccurate quantification in the assessment of haemodynamic changes. To cope with these difficulties, we propose a nonlinear tomographic image reconstruction algorithm for a two-layered slab geometry that uses time-resolved reflected light. The algorithm is based on the previously developed generalized pulse spectrum technique, and implemented within a semi-three-dimensional (3D) framework to conform to the topographic visualization and to reduce computational load. We demonstrate the advantages of the algorithm in quantifying simulated changes in haemoglobin concentrations and investigate its robustness to the uncertainties in the cortical structure and optical properties, as well as the effects of random noises on image quality. The methodology is also validated by experiments using a solid layered phantom.

Semi-three-dimensional algorithm for time-resolved diffuse optical tomography by use of the generalized pulse spectrum technique.

Although a foil three-dimensional (3-D) reconstruction with both 3-D forward and inverse models provide, the optimal solution for diffuse optical tomography (DOT), because of the 3-D nature of photon diffusion in tissue, it is computationally costly for both memory requirement and execution time in a conventional computing environment. Thus in practice there is motivation to develop an image reconstruction algorithm with dimensional reduction based on some modeling approximations. Here we have implemented a semi-3-D modified generalized pulse spectrum technique for time-resolved DOT, where a two-dimensional (2-D) distribution of optical properties is approximately assumed, while we retain 3-D distribution of photon migration in tissue. We have validated the proposed algorithm by reconstructing 3-D structural test objects from both numerically simulated and experimental date. We demonstrate our algorithm by comparing it with the calibrated 2-D reconstruction that is in widespread use as a shortcut to 3-D imaging and proving that the semi-3-D algorithm outperforms the calibrated 2-D algorithm.

Arranging optical fibres for the spatial resolution improvement of topographical images.

Optical topography is a method for visualization of conical activity. Ways of improving the spatial resolution of the topographical image with three arrangements of optical fibres are discussed. A distribution of sensitivity is obtained from the phantom experiment, and used to reconstruct topographical images of an activation area of the brain with the fibres in each arrangement. The correlations between the activated area and the corresponding topographical images are obtained, and the effective arrangement of the optical fibres for improved resolution is discussed.

Maps of optical differential pathlength factor of human adult forehead, somatosensory motor and occipital regions at multi-wavelengths in NIR.

The optical differential pathlength factor (DPF) is an important parameter for physiological measurement using near infrared spectroscopy, but for the human adult head it has been available only for the forehead. Here we report measured DPF results for the forehead, somatosensory motor and occipital regions from measurements on 11 adult volunteers using a time-resolved optical imaging system. The optode separation was about 30 mm and the wavelengths used were 759 nm, 799 nm and 834 nm. Measured DPFs were 7.25 for the central forehead and 6.25 for the temple region at 799 nm. For the central somatosensory and occipital areas (10 mm above the inion), DPFs at 799 nm are 7.5 and 8.75, respectively. Less than 10% decreases of DPF for all these regions were observed when the wavelength increased from 759 nm to 834 nm. To compare these DPF maps with the anatomical structure of the head, a Monte Carlo simulation was carried out to calculate DPF for these regions by using a two-layered semi-infinite model and assuming the thickness of the upper layer to be the sum of the thicknesses of scalp and skull, which was measured from MRI images of a subject's head. The DPF data will be useful for quantitative monitoring of the haemodynamic changes occurring in adult heads.

Imaging of in vitro chicken leg using time-resolved near-infrared optical tomography.

Near-infrared optical imaging gains much attention because of its noninvasiveness and deep penetration depths into tissue. Here, we report near-infrared optical tomographic imaging of an in vitro chicken leg from time-resolved measurements. The in vitro chicken leg, dipped in a cylindrical container filled with diluted Intralipid-10% solution, was imaged with a multichannel time-resolved imaging system. A two-dimensional reconstruction algorithm based on a modified generalized pulse spectrum technique has been developed to reconstruct the images of both the absorption and reduced scattering coefficients simultaneously and quickly. The results demonstrate that a simultaneous reconstruction of absorption and reduced scattering coefficients from time-resolved measurement has a potential to reveal the changes in the optical properties associated with not only the physiological information but also the anatomical structure of the organ.