Validation of the Openwater wearable optical system: cerebral hemodynamic monitoring during a breath-hold maneuver.

Significance: Bedside cerebral blood flow (CBF) monitoring has the potential to inform and improve care for acute neurologic diseases, but technical challenges limit the use of existing techniques in clinical practice. Aim: Here, we validate the Openwater optical system, a novel wearable headset that uses laser speckle contrast to monitor microvascular hemodynamics. Approach: We monitored 25 healthy adults with the Openwater system and concurrent transcranial Doppler (TCD) while performing a breath-hold maneuver to increase CBF. Relative blood flow (rBF) was derived from changes in speckle contrast, and relative blood volume (rBV) was derived from changes in speckle average intensity. Results: A strong correlation was observed between beat-to-beat optical rBF and TCD-measured cerebral blood flow velocity (CBFv), R=0.79; the slope of the linear fit indicates good agreement, 0.87 (95% CI: 0.83 -0.92). Beat-to-beat rBV and CBFv were also strongly correlated, R=0.72, but as expected the two variables were not proportional; changes in rBV were smaller than CBFv changes, with linear fit slope of 0.18 (95% CI: 0.17 to 0.19). Further, strong agreement was found between rBF and CBFv waveform morphology and related metrics. Conclusions: This first in vivo validation of the Openwater optical system highlights its potential as a cerebral hemodynamic monitor, but additional validation is needed in disease states.

Portable cerebral blood flow monitor to detect large vessel occlusion in patients with suspected stroke.

BACKGROUND: Early detection of large vessel occlusion (LVO) facilitates triage to an appropriate stroke center to reduce treatment times and improve outcomes. Prehospital stroke scales are not sufficiently sensitive, so we investigated the ability of the portable Openwater optical blood flow monitor to detect LVO. METHODS: Patients were prospectively enrolled at two comprehensive stroke centers during stroke alert evaluation within 24 hours of onset with National Institutes of Health Stroke Scale (NIHSS) score ≥2. A 70 s bedside optical blood flow scan generated cerebral blood flow waveforms based on relative changes in speckle contrast. Anterior circulation LVO was determined by CT angiography. A deep learning model trained on all patient data using fivefold cross-validation and learned discriminative representations from the raw speckle contrast waveform data. Receiver operating characteristic (ROC) analysis compared the Openwater diagnostic performance (ie, LVO detection) with prehospital stroke scales. RESULTS: Among 135 patients, 52 (39%) had an anterior circulation LVO. The median NIHSS score was 8 (IQR 4-14). The Openwater instrument had 79% sensitivity and 84% specificity for the detection of LVO. The rapid arterial occlusion evaluation (RACE) scale had 60% sensitivity and 81% specificity and the Los Angeles motor scale (LAMS) had 50% sensitivity and 81% specificity. The binary Openwater classification (high-likelihood vs low-likelihood) had an area under the ROC (AUROC) of 0.82 (95% CI 0.75 to 0.88), which outperformed RACE (AUC 0.70; 95% CI 0.62 to 0.78; P=0.04) and LAMS (AUC 0.65; 95% CI 0.57 to 0.73; P=0.002). CONCLUSIONS: The Openwater optical blood flow monitor outperformed prehospital stroke scales for the detection of LVO in patients undergoing acute stroke evaluation in the emergency department. These encouraging findings need to be validated in an independent test set and the prehospital environment.

Validation of the Openwater wearable optical system: cerebral hemodynamic monitoring during a breath hold maneuver.

Bedside cerebral blood flow (CBF) monitoring has the potential to inform and improve care for acute neurologic diseases, but technical challenges limit the use of existing techniques in clinical practice. Here we validate the Openwater optical system, a novel wearable headset that uses laser speckle contrast to monitor microvascular hemodynamics. We monitored 25 healthy adults with the Openwater system and concurrent transcranial Doppler (TCD) while performing a breath-hold maneuver to increase CBF. Relative blood flow (rBF) was derived from the changes in speckle contrast, and relative blood volume (rBV) was derived from the changes in speckle average intensity. A strong correlation was observed between beat-to-beat optical rBF and TCD-measured cerebral blood flow velocity (CBFv), R=0.79; the slope of the linear fit indicates good agreement, 0.87 (95% CI:0.83-0.92). Beat-to-beat rBV and CBFv were strongly correlated, R=0.72, but as expected the two variables were not proportional; changes in rBV were smaller than CBFv changes, with linear fit slope of 0.18 (95% CI:0.17-0.19). Further, strong agreement was found between rBF and CBFv waveform morphology and related metrics. This first in vivo validation of the Openwater optical system highlights its potential as a cerebral hemodynamic monitor, but additional validation is needed in disease states.

Hyperspectral optical tomography of intrinsic signals in the rat cortex.

We introduce a tomographic approach for three-dimensional imaging of evoked hemodynamic activity, using broadband illumination and diffuse optical tomography (DOT) image reconstruction. Changes in diffuse reflectance in the rat somatosensory cortex due to stimulation of a single whisker were imaged at a frame rate of 5 Hz using a hyperspectral image mapping spectrometer. In each frame, images in 38 wavelength bands from 484 to 652 nm were acquired simultaneously. For data analysis, we developed a hyperspectral DOT algorithm that used the Rytov approximation to quantify changes in tissue concentration of oxyhemoglobin ([Formula: see text]) and deoxyhemoglobin (ctHb) in three dimensions. Using this algorithm, the maximum changes in [Formula: see text] and ctHb were found to occur at [Formula: see text] and [Formula: see text] beneath the surface of the cortex, respectively. Rytov tomographic reconstructions revealed maximal spatially localized increases and decreases in [Formula: see text] and ctHb of [Formula: see text] and [Formula: see text], respectively, with these maximum changes occurring at [Formula: see text] poststimulus. The localized optical signals from the Rytov approximation were greater than those from modified Beer-Lambert, likely due in part to the inability of planar reflectance to account for partial volume effects.

Visible spatial frequency domain imaging with a digital light microprojector.

There is a need for cost effective, quantitative tissue spectroscopy and imaging systems in clinical diagnostics and pre-clinical biomedical research. A platform that utilizes a commercially available light-emitting diode (LED) based projector, cameras, and scaled Monte Carlo model for calculating tissue optical properties is presented. These components are put together to perform spatial frequency domain imaging (SFDI), a model-based reflectance technique that measures and maps absorption coefficients (µa) and reduced scattering coefficients (µs') in thick tissue such as skin or brain. We validate the performance of the flexible LED and modulation element (FLaME) system at 460, 530, and 632 nm across a range of physiologically relevant µa values (0.07 to 1.5 mm-1) in tissue-simulating intralipid phantoms, showing an overall accuracy within 11% of spectrophotometer values for µa and 3% for µs'. Comparison of oxy- and total hemoglobin fits between the FLaME system and a spectrophotometer (450 to 1000 nm) is differed by 3%. Finally, we acquire optical property maps of a mouse brain in vivo with and without an overlying saline well. These results demonstrate the potential of FLaME to perform tissue optical property mapping in visible spectral regions and highlight how the optical clearing effect of saline is correlated to a decrease in µs' of the skull.

Determination of the effect of source intensity profile on speckle contrast using coherent spatial frequency domain imaging.

Laser Speckle Imaging (LSI) is fast, noninvasive technique to image particle dynamics in scattering media such as biological tissue. While LSI measurements are independent of the overall intensity of the laser source, we find that spatial variations in the laser source profile can impact measured flow rates. This occurs due to differences in average photon path length across the profile, and is of significant concern because all lasers have some degree of natural Gaussian profile in addition to artifacts potentially caused by projecting optics. Two in vivo measurement are performed to show that flow rates differ based on location with respect to the beam profile. A quantitative analysis is then done through a speckle contrast forward model generated within a coherent Spatial Frequency Domain Imaging (cSFDI) formalism. The model predicts remitted speckle contrast as a function of spatial frequency, optical properties, and scattering dynamics. Comparison with experimental speckle contrast images were done using liquid phantoms with known optical properties for three common beam shapes. cSFDI is found to accurately predict speckle contrast for all beam shapes to within 5% root mean square error. Suggestions for improving beam homogeneity are given, including a widening of the natural beam Gaussian, proper diffusing glass spreading, and flat top shaping using microlens arrays.

Spatial frequency domain tomography of protoporphyrin IX fluorescence in preclinical glioma models.

Multifrequency (0 to 0.3 mm(-1)), multiwavelength (633, 680, 720, 800, and 820 nm) spatial frequency domain imaging (SFDI) of 5-aminolevulinic acid-induced protoporphyrin IX (PpIX) was used to recover absorption, scattering, and fluorescence properties of glioblastoma multiforme spheroids in tissue-simulating phantoms and in vivo in a mouse model. Three-dimensional tomographic reconstructions of the frequency-dependent remitted light localized the depths of the spheroids within 500 µm, and the total amount of PpIX in the reconstructed images was constant to within 30% when spheroid depth was varied. In vivo tumor-to-normal contrast was greater than ∼1.5 in reduced scattering coefficient for all wavelengths and was ∼1.3 for the tissue concentration of deoxyhemoglobin (ctHb). The study demonstrates the feasibility of SFDI for providing enhanced image guidance during surgical resection of brain tumors.

Imaging scattering orientation with spatial frequency domain imaging.

Optical imaging techniques based on multiple light scattering generally have poor sensitivity to the orientation and direction of microscopic light scattering structures. In order to address this limitation, we introduce a spatial frequency domain method for imaging contrast from oriented scattering structures by measuring the angular-dependence of structured light reflectance. The measurement is made by projecting sinusoidal patterns of light intensity on a sample, and measuring the degree to which the patterns are blurred as a function of the projection angle. We derive a spatial Fourier domain solution to an anisotropic diffusion model. This solution predicts the effects of bulk scattering orientation on the amplitude and phase of the projected patterns. We introduce a new contrast function based on a scattering orientation index (SOI) which is sensitive to the degree to which light scattering is directionally dependent. We validate the technique using tissue simulating phantoms, and ex vivo samples of muscle and brain. Our results show that SOI is independent of the overall amount of bulk light scattering and absorption, and that isotropic versus oriented scattering structures can be clearly distinguished. We determine the orientation of subsurface microscopic scattering structures located up to 600 µm beneath highly scattering (µ(') (s) = 1.5 mm(-1)) material.

IMAGING: Focusing light in scattering media.

Combining ultrasonic modulation and optical phase conjugation allows light to be tightly focused in a scattering medium, providing benefits for studies of photophysical, photochemical and photobiological processes.

Quantitative determination of dynamical properties using coherent spatial frequency domain imaging.

Laser speckle imaging (LSI) is a fast, noninvasive method to obtain relative particle dynamics in highly light scattering media, such as biological tissue. To make quantitative measurements, we combine LSI with spatial frequency domain imaging, a technique where samples are illuminated with sinusoidal intensity patterns of light that control the characteristic path lengths of photons in the sample. We use both diffusion and radiative transport to predict the speckle contrast of coherent light remitted from turbid media. We validate our technique by measuring known Brownian diffusion coefficients (D(b)) of scattering liquid phantoms. Monte Carlo (MC) simulations of radiative transport were found to provide the most accurate contrast predictions. For polystyrene microspheres of radius 800 nm in water, the expected and fit D(b) using radiative transport were 6.10E-07 and 7.10E-07 mm²/s, respectively. For polystyrene microspheres of radius 1026 nm in water, the expected and fit D(b) were 4.7E-07 and 5.35 mm²/s, respectively. For scattering particles in water-glycerin solutions, the fit fractional changes in D(b) with changes in viscosity were all found to be within 3% of the expected value.

Quantitative optical tomography of sub-surface heterogeneities using spatially modulated structured light.

We present a wide-field method for obtaining three-dimensional images of turbid media. By projecting patterns of light of varying spatial frequencies on a sample, we reconstruct quantitative, depth resolved images of absorption contrast. Images are reconstructed using a fast analytic inversion formula and a novel correction to the diffusion approximation for increased accuracy near boundaries. The method provides more accurate quantification of optical absorption and higher resolution than standard diffuse reflectance measurements.

Differentiation of benign and malignant breast tumors by in-vivo three-dimensional parallel-plate diffuse optical tomography.

We have developed a novel parallel-plate diffuse optical tomography (DOT) system for three-dimensional in vivo imaging of human breast tumor based on large optical data sets. Images of oxy-, deoxy-, and total hemoglobin concentration as well as blood oxygen saturation and tissue scattering were reconstructed. Tumor margins were derived using the optical data with guidance from radiology reports and magnetic resonance imaging. Tumor-to-normal ratios of these endogenous physiological parameters and an optical index were computed for 51 biopsy-proven lesions from 47 subjects. Malignant cancers (N=41) showed statistically significant higher total hemoglobin, oxy-hemoglobin concentration, and scattering compared to normal tissue. Furthermore, malignant lesions exhibited a twofold average increase in optical index. The influence of core biopsy on DOT results was also explored; the difference between the malignant group measured before core biopsy and the group measured more than 1 week after core biopsy was not significant. Benign tumors (N=10) did not exhibit statistical significance in the tumor-to-normal ratios of any parameter. Optical index and tumor-to-normal ratios of total hemoglobin, oxy-hemoglobin concentration, and scattering exhibited high area under the receiver operating characteristic curve values from 0.90 to 0.99, suggesting good discriminatory power. The data demonstrate that benign and malignant lesions can be distinguished by quantitative three-dimensional DOT.

Imaging complex structures with diffuse light.

We use diffuse optical tomography to quantitatively reconstruct images of complex phantoms with millimeter sized features located centimeters deep within a highly-scattering medium. A non-contact instrument was employed to collect large data sets consisting of greater than 10(7) source-detector pairs. Images were reconstructed using a fast image reconstruction algorithm based on an analytic solution to the inverse scattering problem for diffuse light.

Comparison of diffuse optical tomography of human breast with whole-body and breast-only positron emission tomography.

We acquire and compare three-dimensional tomographic breast images of three females with suspicious masses using diffuse optical tomography (DOT) and positron emission tomography (PET). Co-registration of DOT and PET images was facilitated by a mutual information maximization algorithm. We also compared DOT and whole-body PET images of 14 patients with breast abnormalities. Positive correlations were found between total hemoglobin concentration and tissue scattering measured by DOT, and fluorodeoxyglucose (18F-FDG) uptake. In light of these observations, we suggest potential benefits of combining both PET and DOT for characterization of breast lesions.

Standardized platform for coregistration of nonconcurrent diffuse optical and magnetic resonance breast images obtained in different geometries.

We present a novel methodology for combining breast image data obtained at different times, in different geometries, and by different techniques. We combine data based on diffuse optical tomography (DOT) and magnetic resonance imaging (MRI). The software platform integrates advanced multimodal registration and segmentation algorithms, requires minimal user experience, and employs computationally efficient techniques. The resulting superposed 3-D tomographs facilitate tissue analyses based on structural and functional data derived from both modalities, and readily permit enhancement of DOT data reconstruction using MRI-derived a-priori structural information. We demonstrate the multimodal registration method using a simulated phantom, and we present initial patient studies that confirm that tumorous regions in a patient breast found by both imaging modalities exhibit significantly higher total hemoglobin concentration (THC) than surrounding normal tissues. The average THC in the tumorous regions is one to three standard deviations larger than the overall breast average THC for all patients.

Diffuse optical tomography of breast cancer during neoadjuvant chemotherapy: a case study with comparison to MRI.

We employ diffuse optical tomography (DOT) to track treatment progress in a female subject presenting with locally advanced invasive carcinoma of the breast during neoadjuvant chemotherapy. Three-dimensional images of total hemoglobin concentration and scattering identified the tumor. Our measurements reveal tumor shrinkage during the course of chemotherapy, in reasonable agreement with magnetic resonance images of the same subject. A decrease in total hemoglobin concentration contrast between tumor and normal tissue was also observed over time. The results demonstrate the potential of DOT for measuring physiological parameters of breast lesions during chemotherapy.