Validation of diffuse correlation spectroscopy measurements of rodent cerebral blood flow with simultaneous arterial spin labeling MRI; towards MRI-optical continuous cerebral metabolic monitoring.

Cerebral blood flow (CBF) during stepped hypercapnia was measured simultaneously in the rat brain using near-infrared diffuse correlation spectroscopy (DCS) and arterial spin labeling MRI (ASL). DCS and ASL CBF values agree very well, with high correlation (R=0.86, p< 10(-9)), even when physiological instability perturbed the vascular response. A partial volume effect was evident in the smaller magnitude of the optical CBF response compared to the MRI values (averaged over the cortical area), primarily due to the inclusion of white matter in the optically sampled volume. The 8.2 and 11.7 mm mid-separation channels of the multi-distance optical probe had the lowest partial volume impact, reflecting ~75 % of the MR signal change. Using a multiplicative correction factor, the ASL CBF could be predicted with no more than 10% relative error, affording an opportunity for real-time relative cerebral metabolism monitoring in conjunction with MR measurement of cerebral blood volume using super paramagnetic contrast agents.

Feasibility of NIRS in the neurointensive care unit: a pilot study in stroke using physiological oscillations.

INTRODUCTION: Near-infrared spectroscopy (NIRS) is a non-invasive, real-time bedside modality sensitive to changes in cerebral perfusion and oxygenation and is highly sensitive to physiological oscillations at different frequencies. However, the clinical feasibility of NIRS remains limited, partly due to concerns regarding NIRS signal quantification, which relies on mostly arbitrary assumptions on hemoglobin concentrations and tissue layers. In this pilot study comparing stroke patients to healthy controls, we explored the utility of the interhemispheric correlation coefficient (IHCC) during physiological oscillations in detecting asymmetry in hemispheric microvascular hemodynamics. METHODS: Using bi-hemispheric continuous-wave NIRS, 12 patients with hemispheric strokes and 9 controls were measured prospectively. NIRS signal was band-pass filtered to isolate cardiac (0.7-3 Hz) and respiratory (0.15-0.7 Hz) oscillations. IHCCs were calculated in both oscillation frequency bands. Using Fisher's Z-transform for non-Gaussian distributions, the IHCC during cardiac and respiratory oscillations were compared between both groups. RESULTS: Nine patients and nine controls had data of sufficient quality to be included in the analysis. The IHCCs during cardiac and respiratory oscillations were significantly different between patients versus controls (cardiac 0.79 +/- 0.18 vs. 0.94 +/- 0.07, P = 0.025; respiratory 0.24 +/- 0.28 vs. 0.59 +/- 0.3; P = 0.016). CONCLUSIONS: Computing the IHCC during physiological cardiac and respiratory oscillations may be a new NIRS analysis technique to quantify asymmetric microvascular hemodynamics in stroke patients in the neurocritical care unit. It allows each subject to serve as their own control obviating the need for arbitrary assumptions on absolute hemoglobin concentration. Future clinical applications may include rapid identification of patients with ischemic brain injury in the pre-hospital setting. This promising new analysis technique warrants further validation.

A temporal comparison of BOLD, ASL, and NIRS hemodynamic responses to motor stimuli in adult humans.

In this study, we have preformed simultaneous near-infrared spectroscopy (NIRS) along with BOLD (blood oxygen level dependent) and ASL (arterial spin labeling)-based fMRI during an event-related motor activity in human subjects in order to compare the temporal dynamics of the hemodynamic responses recorded in each method. These measurements have allowed us to examine the validity of the biophysical models underlying each modality and, as a result, gain greater insight into the hemodynamic responses to neuronal activation. Although prior studies have examined the relationships between these two methodologies through similar experiments, they have produced conflicting results in the literature for a variety of reasons. Here, by employing a short-duration, event-related motor task, we have been able to emphasize the subtle temporal differences between the hemodynamic parameters with a high contrast-to-noise ratio. As a result of this improved experimental design, we are able to report that the fMRI measured BOLD response is more correlated with the NIRS measure of deoxy-hemoglobin (R = 0.98; P < 10(-20)) than with oxy-hemoglobin (R = 0.71), or total hemoglobin (R = 0.53). This result was predicted from the theoretical grounds of the BOLD response and is in agreement with several previous works [Toronov, V.A.W., Choi, J.H., Wolf, M., Michalos, A., Gratton, E., Hueber, D., 2001. "Investigation of human brain hemodynamics by simultaneous near-infrared spectroscopy and functional magnetic resonance imaging." Med. Phys. 28 (4) 521-527.; MacIntosh, B.J., Klassen, L.M., Menon, R.S., 2003. "Transient hemodynamics during a breath hold challenge in a two part functional imaging study with simultaneous near-infrared spectroscopy in adult humans". NeuroImage 20 1246-1252.; Toronov, V.A.W., Walker, S., Gupta, R., Choi, J.H., Gratton, E., Hueber, D., Webb, A., 2003. "The roles of changes in deoxyhemoglobin concentration and regional cerebral blood volume in the fMRI BOLD signal" Neuroimage 19 (4) 1521-1531]. These data have also allowed us to examine more detailed measurement models of the fMRI signal and comment on the roles of the oxygen saturation and blood volume contributions to the BOLD response. In addition, we found high correlation between the NIRS measured total hemoglobin and ASL measured cerebral blood flow (R = 0.91; P < 10(-10)) and oxy-hemoglobin with flow (R = 0.83; P < 10(-05)) as predicted by the biophysical models. Finally, we note a significant amount of cross-modality, correlated, inter-subject variability in amplitude change and time-to-peak of the hemodynamic response. The observed co-variance in these parameters between subjects is in agreement with hemodynamic models and provides further support that fMRI and NIRS have similar vascular sensitivity.

Simultaneous recording of task-induced changes in blood oxygenation, volume, and flow using diffuse optical imaging and arterial spin-labeling MRI.

Increased neural activity in brain tissue is accompanied by an array of supporting physiological processes, including increases in blood flow and the rates at which glucose and oxygen are consumed. These responses lead to secondary effects such as alterations in blood oxygenation and blood volume, and are ultimately the primary determinants of the amplitude and temporal signature of the blood oxygenation level-dependent (BOLD) signal used prevalently to map brain function. We have performed experiments using a combination of optical and MRI-based imaging methods to develop a more comprehensive picture of the physiological events accompanying activation of primary motor cortex during a finger apposition task. Temporal profiles for changes in tissue hemoglobin concentrations were qualitatively similar to those observed for MRI-based flow and oxygenation signals. Quantitative analysis of these signals revealed peak changes of +16 +/- 2% for HbO, -13 +/- 2% for HbR, +8 +/- 3% for total Hb, +83 +/- 9% for cerebral blood flow, and +1.4 +/- 0.1% for the BOLD MRI signal. A mass balance model was used to estimate the change in rate of oxidative metabolism implied by the optical and flow measurements, leading to a computed value of +47 +/- 5%. It should be noted that the optical and MRI observations may in general reflect changes over different volumes of tissue. The ratio of fractional changes in oxidative metabolism to fractional change in blood flow was found to be 0.56 +/- 0.08, in general agreement with previous studies of flow-metabolism coupling.

Near-infrared frequency-domain optical spectroscopy and magnetic resonance imaging: a combined approach to studying cerebral maturation in neonatal rabbits.

The neonatal rabbit brain shows prolonged postnatal development both structurally and physiologically. We use noninvasive near-IR frequency-domain optical spectroscopy (NIRS) and magnetic resonance imaging (MRI) to follow early developmental changes in cerebral oxygenation and anatomy, respectively. Four groups of animals are measured: NIRS in normals, MRI in normals, and both NIRS and MRI with hypoxia-ischemia (HI) (diffusion MRI staging). NIRS and/or MRI are performed from P3 (postnatal day=P) up to P76. NIRS is performed on awake animals with a frequency-domain tissue photometer. Absolute values of oxyhemoglobin concentration ([HbO2]), deoxyhemoglobin concentration ([HbR]), total hemoglobin concentration (HbT), and hemoglobin saturation (StO2) are calculated. The brains of all animals appeared to be maturing as shown in the diffusion tensor MRI. Mean optical coefficients (reduced scattering) remained unchanged in all animals throughout. StO2 increased in all animals (40% at P9 to 65% at P43) and there are no differences between normal, HI controls, and HI brains. The measured increase in StO2 is in agreement with the reported increase in blood flow during the first 2 months of life in rabbits. HbT, which reflects blood volume, peaked at postnatal day P17, as expected since the capillary density increases up to P17 when the microvasculature matures.

Improving the diffuse optical imaging spatial resolution of the cerebral hemodynamic response to brain activation in humans.

We compare two geometries of sources and detectors for optimizing the diffuse optical imaging resolution of brain activation in humans. Because of limitations in the instruments' dynamic range, most diffuse optical brain activation images have used only nonoverlapping measurements. We demonstrate theoretically and with a human experiment that a simple geometry of sources and detectors can provide overlapping measurements within the limitation of instrumentation dynamic range and produce an image resolution and localization accuracy that is twofold better.

Non-invasive and quantitative near-infrared haemoglobin spectrometry in the piglet brain during hypoxic stress, using a frequency-domain multidistance instrument.

The frequency-domain multiple-distance (FDMD) method is capable of measuring the absolute absorption and reduced scattering coefficients of optically turbid media. Absolute measurement of absorption at two near-infrared (NIR) wavelengths makes possible the quantitation of tissue haemoglobin concentration and tissue haemoglobin oxygen-saturation (StO2). However, errors are introduced by the uncertainties of background absorption and the dissimilarities between real tissues and the simplified mathematical model on which these measurements are based. An FDMD-based tissue instrument has been used for the monitoring of tissue haemoglobin concentration and oxygenation in the brain of newborn piglets during periods of hypoxia and hyperoxia. These tissue haemoglobin saturation values were compared with arterial saturation (SaO2) and venous saturation (SvO2) measured by blood gas analyses. A linear correlation was observed between StO2 and the average of SaO2 and SvO2. However, StO2 is not equal to any fixed weighted average of SaO2 and SvO2 unless we introduce an effective background tissue absorption. The magnitude of the background absorption was about 0.08 cm(-1) at 758 nm and 0.06 cm(-1) at 830 nm, and it was nearly consistent between piglets. The origin of this 'effective' background absorption may be real, an artefact caused by the application of a simplified model to a complex sample, or a combination of factors.

Role of frequency domain optical spectroscopy in the detection of neonatal brain hemorrhage--a newborn piglet study.

OBJECTIVE: Inability of continuous wave (CW) optical spectroscopy to measure changes in scattering, and the use of an arbitrary rather than an actual baseline, makes the CW method highly susceptible to errors that can lead to a false-positive or false-negative diagnosis. Our objective was to assess whether, and to what extent, the use of quantitative frequency domain spectroscopy would improve our ability to detect and monitor the development of brain hemorrhage. METHODS: A dual-channel frequency-domain tissue spectrometer (Model 96208, ISS, Inc., Champaign, IL) was used to monitor the development of experimental subcortical and periventricular-intraventricular hemorrhage (IVH) in 10 newborn piglets (blood injection model). The multidistance approach was employed to calculate the absorption and reduced scattering coefficients and hemoglobin changes from the ac, dc, and phase values acquired at four different source-detector distances and at 752 nm and 830 nm. RESULTS: There were significant absorption and scattering changes in the subcortical hematoma (n = 5) and the IVH groups (n = 5). The smallest detectable amount of blood in the brain was 0.04 ml. Changes associated with subcortical hematoma were several times higher than those associated with IVH, and correlated better with the estimated cross-sectional area of the hematoma than with the volume of the injected blood. As opposed to IVH, there was a significant absorption difference between the injured (subcortical hematoma) and normal side of the brain, probably because in case of IVH a significant volume of the injected blood had accumulated/spread beyond the reach of the probe. CONCLUSION: Clearly, frequency-domain spectroscopy cannot increase our ability to quantify the volume (size) or the oxygenation of the injected blood, especially in the case of IVH. However, the ability to quantify the baseline tissue absorption and scattering would significantly improve diagnostic performance, and may allow for early identification and treatment of neonatal brain hemorrhage.

Near-infrared study of fluctuations in cerebral hemodynamics during rest and motor stimulation: temporal analysis and spatial mapping.

We have noninvasively studied the motor cortex hemodynamics in human subjects under rest and motor stimulation conditions using a multichannel near-infrared tissue spectrometer. Our instrument measures optical maps of the cerebral cortex at two wavelengths (758 and 830 nm), with an acquisition time of 160 ms per map. We obtained optical maps of oxy- and deoxy-hemoglobin concentration changes in terms of amplitudes of folding average, power spectrum and coherence at the stimulation repetition frequency, and the phase synchronization index. Under periodic motor stimulation conditions, we observed coherence and frequency or phase synchronization of the local hemodynamic changes with stimulation. Our main findings are the following: (1) The amplitude of the hemodynamic response to the motor stimulation is comparable to the amplitude of the fluctuations at rest. (2) The spatial patterns of the oxy- and deoxy-hemoglobin responses to the stimulation are different. (3) The hemodynamic response to stimulation shows a spatial localization and a level of phase synchronization with the motor stimulation that depends on the stimulation period.

On-line optical imaging of the human brain with 160-ms temporal resolution.

We have developed an instrument for non-invasive optical imaging of the human brain that produces on-line images with a temporal resolution of 160 ms. The imaged quantities are the temporal changes in cerebral oxy-hemoglobin and deoxy-hemoglobin concentrations. We report real-time videos of the arterial pulsation and motor activation recorded on a 4 x 9 cm 2 area of the cerebral cortex in a healthy human subject. This approach to optical brain imaging is a powerful tool for the investigation of the spatial and temporal features of the optical signals collected on the brain.

Real-time optical imaging of experimental brain ischemia and hemorrhage in neonatal piglets.

Our objective was to study the development of experimental brain ischemia and hemorrhage by real-time optical imaging. Optical imaging is based on the ability of near infrared light to non-invasively penetrate through the intact scalp and skull and measure brain concentrations of oxy- and deoxyhemoglobin, dominant brain absorbers. Optical imaging was performed in 7 anesthetized, instrumented, and ventilated newborn piglets subjected to the injection of 0.3 cc of saline followed by 2 cc of blood into the left frontal subcortical brain region via a needle inserted through the skull with stereotactic guidance. The image-acquisition rate of 5.26 images per sec allowed for real-time imaging. The detection threshold of the imager at the estimated depth of 1-1.5 cm was approximately 70 microL for saline and approximately 40 microL for blood. The imager readily detected five subcortical hematomas and two large bilateral subarachnoid hemorrhages. The imager detected a global decrease in brain absorption associated with the volume-injection-related increase in intracranial pressure in the surrounding ipsilateral and contralateral brain. Any decrease in brain absorption is an equivalent to brain ischemia. This study demonstrates the capability of optical imaging in detecting brain ischemia and hemorrhage in real-time with high temporal and spatial resolution.

Non-invasive optical monitoring of the newborn piglet brain using continuous-wave and frequency-domain spectroscopy.

We have used continuous-wave (CW) and frequency-domain spectroscopy to investigate the optical properties of the newborn piglet brain in vivo and non-invasively. Three anaesthetized, intubated, ventilated and instrumented newborn piglets were placed into a stereotaxic instrument for optimal experimental stability, reproducible probe-to-scalp optical contact and 3D adjustment of the optical probe. By measuring the absolute values of the brain absorption and reduced scattering coefficients at two wavelengths (758 and 830 nm), frequency-domain spectroscopy provided absolute readings (in contrast to the relative readings of CW spectroscopy) of cerebral haemoglobin concentration and saturation during experimentally induced perturbations in cerebral haemodynamics and oxygenation. Such perturbations included a modulation of the inspired oxygen concentration, transient brain asphyxia, carotid artery occlusion and terminal brain asphyxia. The baseline cerebral haemoglobin saturation and concentration, measured with frequency-domain spectroscopy, were about 60% and 42 microM respectively. The cerebral saturation values ranged from a minimum of 17% (during transient brain asphyxia) to a maximum of 80% (during recovery from transient brain asphyxia). To analyse the CW optical data, we have (a) derived a mathematical relationship between the cerebral optical properties and the differential pathlength factor and (b) introduced a method based on the spatial dependence of the detected intensity (dc slope method). The analysis of the cerebral optical signals associated with the arterial pulse and with respiration demonstrates that motion artefacts can significantly affect the intensity recorded from a single optode pair. Motion artefacts can be strongly reduced by combining data from multiple optodes to provide relative readings in the dc slope method. We also report significant biphasic changes (initial decrease and successive increase) in the reduced scattering coefficient measured in the brain after the piglet had been sacrificed.

Application of near-infrared tissue oxymetry to the diagnosis of peripheral vascular disease.

Near-infrared spectroscopy (NIRS) is a noninvasive technique to measure the tissue oxygenation in real time. This optical method has many advantages over the invasive analysis currently used for clinical tests. Among the possible applications of near-infrared oxymetry, we report three protocols (exercise, venous occlusion and tilting table) in conjunction with NIRS, and discuss their applicability in the diagnosis of peripheral vascular disease (PVD).

Noninvasive optical method of measuring tissue and arterial saturation: an application to absolute pulse oximetry of the brain.

We present a frequency-domain optical method for real-time noninvasive measurement of absolute tissue and arterial saturation. This method is based on quantitative measurement of the tissue absorption spectrum (for tissue saturation) and of the amplitude of the arterial-pulsation-induced absorption oscillations (for arterial saturation) at eight wavelengths in the range 633-841 nm. We report results obtained from readings taken from the forehead of a healthy volunteer, showing baseline saturation values of 74.7+/-0.2% (tissue) and 96.9+/-0.5% (arterial). These values dropped to minimum values of 71.6+/-0.2% and 90.0+/-0.2% , respectively, after 1 min of reduced inspired oxygen concentration [10% (by volume) O(2) from a baseline value of 21% O(2) ].

Assessment of the size, position, and optical properties of breast tumors in vivo by noninvasive optical methods.

We present a method for the noninvasive determination of the size, position, and optical properties (absorption and reduced scattering coefficients) of tumors in the human breast. The tumor is first detected by frequency-domain optical mammography. It is then sized, located, and optically characterized by use of diffusion theory as amodel for the propagation of near-infrared light in breast tissue. Our method assumes that the tumor is a spherical inhomogeneity embedded in an otherwise homogeneous tissue. We report the results obtained on a 55-year-old patient with a papillary cancer in the right breast. We found that the tumor absorbs and scatters near-infrared light more strongly than the surrounding healthytissue. Our method has yielded a tumor diameter of 2.1 ? 0.2cm, which is comparable with the actual size of 1.6 cm, determined after surgery. From the tumor absorption coefficients at two wavelengths (690 and 825 nm), we calculated the total hemoglobin concentration (40 ? 10 muM) and saturation (71 ? 9%) of the tumor. These results can provide the clinical examiner with more detailed information about breast lesions detected by frequency-domain optical mammography, thereby enhancing its potential for specificity.

Influence of a superficial layer in the quantitative spectroscopic study of strongly scattering media.

We have experimentally investigated the meaning of the effective optical absorption [mu(a)((eff))] and the reduced scattering [mu(s)?((eff))] coefficients measured on the surfaces of two-layered turbid media, using the diffusion equation for homogeneous, semi-infinite media. We performed frequency-domain spectroscopy in a reflectance geometry, using source-detector distances in the range 1.5-4.5 cm. We measured 100 samples, each made of one layer (thickness in the range 0.08-1.6 cm) on top of one semi-infinite block. The optical properties of the samples were similar to those of soft tissues in the near infrared. We found that the measured effective optical coefficients are representative of the underlying block if the superficial layer is less than ~0.4 cm thick, whereas they are representative of the superficial layer if it is more than ~1.3 cm thick.

Contrast features of breast cancer in frequency-domain laser scanning mammography.

Frequency-domain optical mammography has been advocated to improve contrast and thus cancer detectability in breast transillumination. To the best of our knowledge, this report provides the first systematic clinical results of a frequency-domain laser scanning mammograph (FLM). The instrument provides monochromatic light at 690 and 810 nm, whose intensity is modulated at 110.0010 and 110.0008 MHz, respectively. The breast is scanned by stepwise positioning of source and detector, and amplitude and phase for both wavelengths are measured by a photomultiplier tube using heterodyne detection. Images are formed representing amplitude or phase data on linear gray scales. Furthermore, various algorithms carrying on more than one signal (amplitude ratio, phase difference, µa,µs',N) were essayed. Twenty visible cancers out of 25 cancers in the first 59 investigations were analyzed for their quantitative contrast with respect to the whole breast or to defined reference areas. Contrast definitions refer to the signal itself (definition 1), to the signal noise (definition 2), or were based on nonparametric comparison (definition 3). The amplitude signal provides better contrast than the phase signal. Ratio images between red and infrared amplitudes gave variable results; in some cases the tumor contrast was canceled. The algorithms to determine µa and µs' from amplitude and phase data did not significantly improve upon objective contrast. The N algorithm, using the phase signal to flatten the amplitude signal did significantly improve upon contrast according to contrast definitions 1 and 2, however, did not improve upon nonparametric contrast. Thus, with the current instrumentation, the phase signal is helpful to correct for the complex and variable geometry of the breast. However, an independent informational content for tumor differentiation could not be determined. The flat field algorithm did greatly enhance optical contrast in comparison with amplitude or amplitude ratio images. Further evaluation of FLM will have to be based on the N-algorithm images. © 1998 Society of Photo-Optical Instrumentation Engineers.

Measurements of scattering and absorption changes in muscle and brain.

Non-invasive techniques for the study of human brain function based on changes of the haemoglobin content or on changes of haemoglobin saturation have recently been proposed. Among the new methods, near-infrared transmission measurements may have significant advantages and complement well-established methods such as functional magnetic resonance imaging and positron emission tomography. Near-infrared measurements can be very fast, comparable in speed to electrophysiological measurements, bur are better localized. We will present the demonstration of measurements of millisecond signals due to brain activity in humans following stimulation of the visual cortex. However, major unresolved questions remain about the origin of the signals observed. Optical measurements on exposed cortex in animals show that both the absorption and the scattering coefficient are affected by neural activity. Model calculations show that the signals we detected may originate from rapid changes of the scattering coefficient in a region about 1 to 2 cm below the scalp. We discuss our measurement protocol, which is based on a frequency-domain instrument, and the algorithm to separate the absorption from the scattering contribution in the overall response. Our method produces excellent separation between scattering and absorption in relatively homogeneous masses such as large muscles. The extrapolation of our measurement protocol to a complex structure such as the human head is critically evaluated.

Frequency-domain techniques enhance optical mammography: initial clinical results.

We present a novel approach to optical mammography and initial clinical results. We have designed and developed a frequency-domain (110-MHz) optical scanner that performs a transillumination raster scan of the female breast in approximately 3 min. The probing light is a dual-wavelength (690 and 810 nm, 10-mW average power), 2-mm-diameter laser beam, and the detection optical fiber is 5 mm in diameter. The ac amplitude and phase data are processed with use of an algorithm that performs edge effect corrections, thereby enhancing image contrast. This contrast enhancement results in a greater tumor detectability compared with simple light intensity images. The optical mammograms are displayed on a computer screen in real time. We present x-ray and optical mammograms from two patients with breast tumors. Our initial clinical results show that the frequency-domain scanner, even at the present stage of development, has the potential to be a useful tool in mammography.