Noninvasive imaging of in vivo blood flow velocity using optical Doppler tomography

We report the development of an optical technique for noninvasive imaging of in vivo blood flow dynamics and tissue structures with high spatial resolution (2-10 microm) in biological systems. The technique is based on optical Doppler tomography (ODT), which combines Doppler velocimetry with optical coherence tomography to measure blood flow velocity at discrete spatial locations. The exceptionally high resolution of ODT permits noninvasive in vivo imaging of both blood microcirculation and tissue structures surrounding the vessel, which has significance for biomedical research and clinical applications. Tomographic imaging of in vivo blood flow velocity in the chick chorioallantoic membrane and in rodent skin is demonstrated.     

Nonlinear responses of cerebral blood volume, blood flow and blood oxygenation signals during visual stimulation

Hemodynamic-based functional magnetic resonance imaging (fMRI) techniques provide a great utility for noninvasive functional brain mapping. However, because the hemodynamic signals reflect underlying neural activity indirectly, characterization of these signals following brain activation is essential for experimental design and data interpretation. In this report, the linear (or nonlinear) responses to neuronal activation of three hemodynamic parameters based primarily on changes of cerebral blood volume, blood flow and blood oxygenation were investigated by testing these hemodynamic responses' additivity property. Using a recently developed fMRI technique that acquires vascular space occupancy (VASO), arterial spin labeling (ASL) perfusion and blood oxygenation level-dependent (BOLD) signals simultaneously, the additivity property of the three hemodynamic responses in human visual cortex was assessed using various visual stimulus durations. Experiments on healthy volunteers showed that all three hemodynamic-weighted signals responded nonlinearly to stimulus durations less than 4 s, with the degree of nonlinearity becoming more severe as the stimulus duration decreased. Vascular space occupancy and ASL perfusion signals showed similar nonlinearity properties, whereas the BOLD signal was the most nonlinear. These data suggest that caution should be taken in the interpretation of hemodynamic-based signals in fMRI.     

Monte Carlo simulation of light propagation in adult brain: influence of tissue blood content and indocyanine green

Near-infrared spectroscopy (NIRS), applied to a human head, is a noninvasive method in neurointensive care to monitor cerebral hemodynamics and oxygenation. The method is particularly powerful when it is applied in combination with indocyanine green (ICG) as a tracer substance. In order to assess contributions to the measured optical density (OD) which are due to extracerebral circulation and disturb the clinically significant intracerebral signals, we simulated the light propagation in an anatomically representative model of the adult head derived from MRI measurements with the aid of Monte Carlo methods. Since the measured OD signal depends largely on the relative blood content in various transilluminated tissues, we weighted the calculated densities of the photon distribution under baseline conditions within the tissues with the changes and aberrations of the relative blood volumes which we expect to prevail under physiological conditions. Furthermore, the influence of the IGC dye as a tracer substance was assessed. We conclude that up to about different 70% of the measured OD signal may have its origin in the tissues of interest under optimal conditions, which is mainly due to the extrapolated high relative blood content of brain tissue along with the influence of ICG.     

皮肤微循环无损伤光学成像技术的新进展

微循环信息的获取对于各类疾病的诊断和治疗有着及其重要的作用。皮肤微循环无损伤成像技术取得了很大的进展,出现了各种非光学方法(核磁共振成像、正电子发射断层成像术、超声波成像等)和光学方法(共焦显微镜、光学相干断层摄影术、新型的正交偏振光谱成像技术等)。主要介绍了皮肤微循环无损伤光学成像技术的新进展。     

Noninvasive optical control of complex semiconductor laser dynamics

Time-delayed feedback control (TDFC) is transferred to the optical domain and applied to complex multisection semiconductor lasers as used in optical communication. Pyragas-type control is provided by purely optical feedback from an external Fabry-Pérot interferometer. This all-optical setup needs no time-consuming signal processing and, thus, has practically no speed limit. Proof-of-principle experiments demonstrate noninvasive stabilization of unstable steady states, chaos control, and suppression of noise-induced oscillations on picosecond time scales. A Lang-Kobayashi type model with optical TDFC is investigated taking into account the dynamic details of the device as well as all-optical time-delayed feedback. The parameter regimes that allow for stabilization of stationary emission are mapped out in good agreement with the experiments. Including noise, an analytical expression for the power spectral density is derived, which is confirmed by the experimental all-optical suppression of noise-induced relaxation oscillations.     

Balanced steady state free precession for arterial spin labeling MRI: Initial experience for blood flow mapping in human brain,retina, and kidney

We implemented pseudo-continuous ASL (pCASL) with 2D and 3D balanced steady state free precession (bSSFP) readout for mapping blood flow in the human brain, retina, and kidney, free of distortion and signal dropout, which are typically observed in the most commonly used echo-planar imaging acquisition. High resolution functional brain imaging in the human visual cortex was feasible with 3D bSSFP pCASL. Blood flow of the human retina could be imaged with pCASL and bSSFP in conjunction with a phase cycling approach to suppress the banding artifacts associated with bSSFP. Furthermore, bSSFP based pCASL enabled us to map renal blood flow within a single breath hold. Control and test–retest experiments suggested that the measured blood flow values in retina and kidney were reliable. Because there is no specific imaging tool for mapping human retina blood flow and the standard contrast agent technique for mapping renal blood flow can cause problems for patients with kidney dysfunction, bSSFP based pCASL may provide a useful tool for the diagnosis of retinal and renal diseases and can complement existing imaging techniques.     

In vivo measurement of tissue damage, oxygen saturation changes and blood flow changes after experimental traumatic brain injury in rats using susceptibility weighted imaging

Traumatic brain injury (TBI) is a prevalent disease, and many TBI patients experience disturbed cerebral blood flow (CBF) after injury. Moreover, TBI is difficult to quantify with conventional imaging modalities. In this paper, we utilized susceptibility weighted imaging (SWI) as a means to monitor functional blood oxygenation changes and to quantify CBF changes in animals after trauma. In this study using six rats, brain trauma was induced by a weight drop model and the brain was scanned over four time points: pre trauma, and 4 h, 24 h and 48 h post trauma. Five rats survived and one died after trauma. A blood phase analysis using filtered SWI phase images suggested that three rats recovered after 48 h and two rats deteriorated. SWI also suggested that CBF decreased by up to 26%. The CBF change is in agreement with the results of arterial spin labeling methods conducted in this study and with previously published results. Furthermore, SWI revealed an enlargement of the major venous vasculature in deep brain structures, in accordance with the location of diffuse axonal injury. Compared with the traditional, invasive, clinical monitoring of cerebral vascular damage and reduction in blood flow, this method offers a novel, safe and noninvasive approach to quantify changes in oxygen saturation and CBF and to visualize structural changes in blood vasculature after TBI.     

A nonlinear model for calibration of blood glucose noninvasive measurement using near infrared spectroscopy

In order to improve prediction accuracy of calibration in human blood glucose noninvasive measurement using near infrared (NIR) spectroscopy, a modified uninformative variable elimination (mUVE) method combined with kernel partial least squares (KPLS), named as mUVE–KPLS, is proposed as an alternative nonlinear modeling strategy. Under the mUVE method, high-frequency noise and matrix background can be eliminated simultaneously, which provide a optimized data for calibration in sequence; under the kernel trick, a nonlinear relationship of response variable and predictor variables is constructed, which is different with PLS that is a complex model and inappropriate to describe the underlying data structure with significant nonlinear characteristics. Two NIR spectra data of basic research experiments (simulated physiological solution samples experiment in vitro and human noninvasive measurement experiment in vivo) are introduced to evaluate the performance of the proposed method. The results indicate that, after elimination high-frequency noise and matrix background from optical absorption of water in NIR region, a high-quality spectra data is employed in calibration; and under the selection of kernel function and kernel parameter, the best prediction accuracy can be got by KPLS with Gaussian kernel compared with Spline-PLS and PLS. It is encouraging that mUVE–KPLS is a promising nonlinear calibration strategy with higher prediction accuracy for blood glucose noninvasive measurement using NIR spectroscopy.     

Phase-resolved functional optical coherence tomography: simultaneous imaging of in situ tissue structure, blood flow velocity, standard deviation, birefringence, and Stokes vectors in human skin

We describe a phase-resolved functional optical coherence tomography system that can simultaneously yieldin situ images of tissue structure, blood flow velocity, standard deviation, birefringence, and the Stokes vectors in human skin. Multifunctional images were obtained by processing of analytical interference fringe signals derived from two perpendicular polarization-detection channels. The blood flow velocity and standard deviation images were obtained by comparison of the phases from pairs of analytical signals in neighboring A-lines in the same polarization state. The analytical signals from two polarization-diversity detection channels were used to determine the four Stokes vectors for four reference polarization states. From the four Stokes vectors, the birefringence image, which is not sensitive to the orientation of the optical axis in the sample, was obtained. Multifunctional in situ images of a port wine stain birthmark in human skin are presented.     

Laser optical method of visualizing cutaneous blood vessels and its applications in biometry and photomedicine

We propose and examine a new approach to visualizing a local network of cutaneous blood vessels using laser optical methods for applications in biometry and photomedicine. Various optical schemes of the formation of biometrical information on the architecture of blood vessels of skin tissue are analyzed. We developed an optical model of the interaction of the laser radiation with the biological tissue and a mathematical algorithm of processing of measurement results. We show that, in medicine, the visualization of blood vessels makes it possible to calculate and determine regions of disturbance of blood microcirculation and to control tissue hypoxia, as well as to maintain the local concentration of oxygen at a level necessary for the normal cellular metabolism. We propose noninvasive optical methods for modern photomedicine and biometry for diagnostics and elimination of tissue hypoxia and for personality identification and verification via the pattern of cutaneous blood vessels.     

Cerebral blood flow imaged with ultrahigh-resolution optical coherence angiography and Doppler tomography

Speckle contrast based optical coherence angiography (OCA) and optical coherence Doppler tomography (ODT) have been applied to image cerebral blood flow previously. However, the contrast mechanisms of these two methods are not fully studied. Here, we present both flow phantom and in vivo animal experiments using ultrahigh-resolution OCA (μOCA) and ODT (μODT) to investigate the flow sensitivity differences between these two methods. Our results show that the high sensitivity of μOCA for visualizing minute vasculature (e.g., slow capillary beds) is due to the enhancement by random Brownian motion of scatterers (e.g., red and white blood cells) within the vessels; whereas, μODT permits detection of directional flow below the Brownian motion regime (e.g., laser-induced microischemia) and is, therefore, more suitable for brain functional imaging.     

Optical coherence Doppler tomography quantifies laser speckle contrast imaging for blood flow imaging in the rat cerebral cortex

A dual-imaging modality is demonstrated for high-resolution quantitative imaging of local cerebral blood flow in the rat cortex by combining simultaneous spectral-domain Doppler optical coherence tomography (SDOCT) and full-field laser speckle contrast imaging (LSCI). Preliminary studies in tissue flow phantom and cocaine-induced cerebral blood flow changes indicated that by correlating coregistered cortical arterial blood flow, the relative measurement of flow changes by LSCI could be accurately calibrated by the absolute flow imaging provided by SDOCT (least square fit, r(2) approximately 0.96). Quantitative LSCI of cerebral blood flow is crucial to the quantitative analyses of the spatiotemporal hemodynamics of functional brain activations and thus improved understanding of neural process.     

Phase-resolved optical coherence tomography and optical Doppler tomography for imaging blood flow in human skin with fast scanning speed and high velocity sensitivity

We have developed a novel phase-resolved optical coherence tomography (OCT) and optical Doppler tomography (ODT) system that uses phase information derived from a Hilbert transformation to image blood flow in human skin with fast scanning speed and high velocity sensitivity. Using the phase change between sequential scans to construct flow-velocity imaging, this technique decouples spatial resolution and velocity sensitivity in flow images and increases imaging speed by more than 2 orders of magnitude without compromising spatial resolution or velocity sensitivity. The minimum flow velocity that can be detected with an axial-line scanning speed of 400 Hz and an average phase change over eight sequential scans is as low as 10 microm/s, while a spatial resolution of 10 microm is maintained. Using this technique, we present what are to our knowledge the first phase-resolved OCT/ODT images of blood flow in human skin.     

基于扩散相关光谱的血流检测方法研究

组织血流信息在临床诊断和治疗中具有重要的作用,无创血流检测是医患双方的期望。研究采用了近红外扩散相关光谱方法对生物组织血流进行无创检测,理论分析了散射光斑强度的变化和被测组织中血细胞运动状态的函数关系,建立了检测组织血流的理论模型及检测系统。该系统通过求解组织表面散射光斑电场强度的时间自相关函数来推断组织中血细胞的运动状态,进行组织血流的定量分析。采用健康人体前臂袖带加压实验模型对该系统进行了验证,实验结果验证了该系统进行组织无创血流检测的可行性,同时也表明该系统可以提供从浅层到深层的组织血流变化信息。     

A study of light scattering of mononuclear blood cells with scanning flow cytometry

This study describes the measurement of light scattering of human mononuclear blood cells, the development of an appropriate optical model for those cells, and solution of the inverse light-scattering problem. The angular dependency of light-scattering intensity of mononuclear blood cells was experimentally measured by means of scanning flow cytometry. A sphere consisting of several concentric homogeneous layers with different refractive indices was tested as an optical model for mononuclear blood cells. A five-layer model has given the best agreement between experimental and theoretical light-scattering profiles. The inverse light-scattering problem was solved for a five-layer model with an optimization procedure that allows one to retrieve cell parameters: cell size relates to the outer diameter of the fifth layer; size of the nucleus relates to the outer diameter of the third layer. Mean values of cell size, nuclear size, refractive indices of nucleus and cellular cytoplasm were determined for blood monocytes and lymphocytes.     

Atlas-based and DTI-guided quantification of human brain cerebral blood flow: Feasibility,quality assurance,spatial heterogeneity and age effects

Accurate and noninvasive quantification of regional cerebral blood perfusion (CBF) of the human brain tissue would advance the study of the complex interplay between human brain structure and function, in both health and disease. Despite the plethora of works on CBF in gray matter, a detailed quantitative white matter perfusion atlas has not been presented on healthy adults using the International Consortium for Brain Mapping atlases. In this study, we present a host of assurance measures such as temporal stability, spatial heterogeneity and age effects of regional and global CBF in selected deep, cortical gray matter and white matter tracts identified and quantified using diffusion tensor imaging (DTI). We utilized whole brain high-resolution DTI combined with arterial spin labeling to quantify regional CBF on 15 healthy adults aged 23.2–57.1 years. We present total brain and regional CBF, corresponding volume, mean diffusivity and fractional anisotropy spatial heterogeneity, and dependence on age as additional quality assurance measures to compare with published trends using both MRI and nuclear medicine methods. Total CBF showed a steady decrease with age in gray matter (r=?0.58; P= .03), whereas total CBF of white matter did not significantly change with age (r= 0.11; P= .7). This quantitative report offers a preliminary baseline of CBF, volume and DTI measurements for the design of future multicenter and clinical studies utilizing noninvasive perfusion and DT-MRI.     

Effect of high dose isoflurane on cerebral blood flow in macaque monkeys

The effect of high dose isoflurane on cerebral blood flow (CBF) was investigated in adult macaque monkeys receiving 1% to 2% isoflurane with the pseudo continuous arterial-spin-labeling (pCASL) MRI technique. High concentration (2%) of isoflurane resulted in significant increase in the mean CBF of the global, cortical, subcortical regions and the regional CBF in all subcortical structures and most cortical structures (such as motor cortex, anterior cingulate cortex, but not media prefrontal cortex). In addition, the changes of regional CBF in the affected regions correlated linearly with increasing isoflurane concentrations. The study demonstrates region-specific CBF abnormal increase in adult macaque monkeys under high dose (2%) isoflurane and suggests that the brain functionality in the corresponding structures may be affected and need to be taken consideration in either human or non-human primate neuroimaging studies.     

改进的同步迭代算法在光声血管成像中的应用

光声成像结合了光学成像和声学成像的优点，是一种高分辨率，高对比度的无损伤医学成像技术.一种改进的同步迭代算法应用于光声图像重建.仿真和模拟结果表明，与传统的代数迭代算法相比，在90°，135°，180°的有限场光声成像中，此算法对测量误差的校正和迭代次数的收敛上具有较大的优势，图像重建的速度和成像质量都有了明显的提高.实验中，一种圆形扫描结构的光声成像装置，用于180°的有限场扫描，利用改进的同步迭代算法，重建出了高对比度和高分辨率（60μm）的鸡胚胎光声血管图像.实验证明，这种算法的应用，大幅度减少了数据采集时间，为光声成像技术运用于实时监测血流灌注和肿瘤光动力治疗的血管损伤效应提供了潜在的应用价值. 关键词： 光声成像 有限角度 代数迭代算法 光声血管成像     

Simultaneous imaging of total cerebral hemoglobin concentration,oxygenation, and blood flow during functional activation

A simple instrument is demonstrated for high-resolution simultaneous imaging of total hemoglobin concentration and oxygenation and blood flow in the brain by combining rapid multiwavelength imaging with laser speckle contrast imaging. The instrument was used to image changes in oxyhemoglobin and deoxyhemoglobin and blood flow during cortical spreading depression and single whisker stimulation in rats through a thinned skull. The ability to image blood flow and hemoglobin concentration changes simultaneously with high resolution will permit detailed quantitative analysis of the spatiotemporal hemodynamics of functional brain activation, including imaging of oxygen metabolism. This is of significance to the neuroscience community and will lead to a better understanding of the interrelationship of neural, metabolic, and hemodynamic processes in normal and diseased brains.     

Diffuse optical measurement of blood flow in breast tumors

Blood flow contrast between tumor and normal tissues in patients with malignant and benign breast cancer was measured by diffuse optical correlation methods. The measurements were carried out with a hand-held optical probe that was manually scanned over the tumor-bearing breast. Increased blood flow was observed in tumor regions relative to healthy tissue, and control subjects did not exhibit significant blood flow heterogeneity. The measurements introduce a new optical contrast for diffuse optical mammography.