Validation of diffuse correlation spectroscopy measures of critical closing pressure against transcranial Doppler ultrasound in stroke patients.

SIGNIFICANCE: Intracranial pressure (ICP), variability in perfusion, and resulting ischemia are leading causes of secondary brain injury in patients treated in the neurointensive care unit. Continuous, accurate monitoring of cerebral blood flow (CBF) and ICP guide intervention and ultimately reduce morbidity and mortality. Currently, only invasive tools are used to monitor patients at high risk for intracranial hypertension. AIM: Diffuse correlation spectroscopy (DCS), a noninvasive near-infrared optical technique, is emerging as a possible method for continuous monitoring of CBF and critical closing pressure (CrCP or zero-flow pressure), a parameter directly related to ICP. APPROACH: We optimized DCS hardware and algorithms for the quantification of CrCP. Toward its clinical translation, we validated the DCS estimates of cerebral blood flow index (CBFi) and CrCP in ischemic stroke patients with respect to simultaneously acquired transcranial Doppler ultrasound (TCD) cerebral blood flow velocity (CBFV) and CrCP. RESULTS: We found CrCP derived from DCS and TCD were highly linearly correlated (ipsilateral R2 = 0.77, p = 9 × 10 - 7; contralateral R2 = 0.83, p = 7 × 10 - 8). We found weaker correlations between CBFi and CBFV (ipsilateral R2 = 0.25, p = 0.03; contralateral R2 = 0.48, p = 1 × 10 - 3) probably due to the different vasculature measured. CONCLUSION: Our results suggest DCS is a valid alternative to TCD for continuous monitoring of CrCP.

The role of diffuse correlation spectroscopy and frequency-domain near-infrared spectroscopy in monitoring cerebral hemodynamics during hypothermic circulatory arrests.

OBJECTIVES: Real-time noninvasive monitoring of cerebral blood flow (CBF) during surgery is key to reducing mortality rates associated with adult cardiac surgeries requiring hypothermic circulatory arrest (HCA). We explored a method to monitor cerebral blood flow during different brain protection techniques using diffuse correlation spectroscopy (DCS), a noninvasive optical technique which, combined with frequency-domain near-infrared spectroscopy (FDNIRS), also provides a measure of oxygen metabolism. METHODS: We used DCS in combination with FDNIRS to simultaneously measure hemoglobin oxygen saturation (SO2), an index of cerebral blood flow (CBFi), and an index of cerebral metabolic rate of oxygen (CMRO2i) in 12 patients undergoing cardiac surgery with HCA. RESULTS: Our measurements revealed that a negligible amount of blood is delivered to the cerebral cortex during HCA with retrograde cerebral perfusion, indistinguishable from HCA-only cases (median CBFi drops of 93% and 95%, respectively) with consequent similar decreases in SO2 (mean decrease of 0.6 ± 0.1% and 0.9 ± 0.2% per minute, respectively); CBFi and SO2 are mostly maintained with antegrade cerebral perfusion; the relationship of CMRO2i to temperature is given by CMRO2i = 0.052e0.079T. CONCLUSIONS: FDNIRS-DCS is able to detect changes in CBFi, SO2, and CMRO2i with intervention and can become a valuable tool for optimizing cerebral protection during HCA.

Erratum: Prolonged monitoring of cerebral blood flow and autoregulation with diffuse correlation spectroscopy in neurocritical care patients.

[This corrects the article DOI: 10.1117/1.NPh.5.4.045005.].

Diffuse correlation spectroscopy and frequency-domain near-infrared spectroscopy for measuring microvascular blood flow in dynamically exercising human muscles.

In the last 20 yr, near-infrared diffuse correlation spectroscopy (DCS) has been developed for providing a noninvasive estimate of microvascular blood flow (BF) as a BF index (BFi) in the human skin, muscle, breast, brain, and other tissue types. In this study, we proposed a new motion correction algorithm for DCS-derived BFi able to remove motion artifacts during cycling exercise. We tested this algorithm on DCS data collected during cycling exercise and demonstrated that DCS can be used to quantify muscle BFi during dynamic high-intensity exercise. In addition, we measured tissue regional oxygen metabolic rate (MRO2i) by combining frequency-domain multidistance near-infrared spectroscopy (FDNIRS) oximetry with DCS flow measures. Recreationally active subjects (n = 12; 31 ± 8 yr, 183 ± 4 cm, 79 ± 10 kg) pedaled at 80-100 revolutions/min until volitional fatigue with a work rate increase of 30 W every 4 min. Exercise intensity was normalized in each subject to the cycling power peak (Wpeak). Both rectus femoris BFi and MRO2i increased from 15% up to 75% Wpeak and then plateaued to the end of the exercise. During the recovery at 30 W cycling power, BFi remained almost constant, whereas MRO2i started to decrease. The BFi/MRO2i plateau was associated with the rising of the lactate concentration, indicating the progressive involvement of the anaerobic metabolism. These findings further highlight the utility of DCS and FDNIRS oximetry as effective, reproducible, and noninvasive techniques to assess muscle BFi and MRO2i in real time during a dynamic exercise such as cycling.NEW & NOTEWORTHY To the best of our knowledge, this study is the first to demonstrate that diffuse correlation spectroscopy in combination with frequency-domain near-infrared spectroscopy can monitor human quadriceps microvascular blood flow and oxygen metabolism with high temporal resolution during a cycling exercise. The optically measured parameters confirm the expected relationship between blood flow, muscle oxidative metabolism, and lactate production during exercise.

Validation of a novel wearable, wireless technology to estimate oxygen levels and lactate threshold power in the exercising muscle.

There is a growing interest in monitoring muscle oxygen saturation (SmO2 ), which is a localized measure of muscle oxidative metabolism and can be acquired continuously and noninvasively using near-infrared spectroscopy (NIRS) methods. Most NIRS systems are cumbersome, expensive, fiber coupled devices, with use limited to lab settings. A novel, low cost, wireless, wearable has been developed for use in athletic training. In this study, we evaluate the advantages and limitations of this new simple continuous-wave (CW) NIRS device with respect to a benchtop, frequency-domain near-infrared spectroscopy (FDNIRS) system. Oxygen saturation and hemoglobin/myoglobin concentration in the exercising muscles of 17 athletic individuals were measured simultaneously with the two systems, while subjects performed an incremental test on a stationary cycle ergometer. In addition, blood lactate concentration was measured at the end of each increment with a lactate analyzer. During exercise, the correlation coefficients of the SmO2 and hemoglobin/myoglobin concentrations between the two systems were over 0.70. We also found both systems were insensitive to the presence of thin layers of varying absorption, mimicking different skin colors. Neither system was able to predict the athletes' lactate threshold power accurately by simply using SmO2 thresholds. Instead, the proprietary software of the wearable device was able to predict the athletes' lactate threshold power within half of one power increment of the cycling test. These results indicate this novel wearable device may provide a physiological indicator of athlete's exertion.

Development and characterization of a multidistance and multiwavelength diffuse correlation spectroscopy system.

This paper presents a multidistance and multiwavelength diffuse correlation spectroscopy (DCS) approach and its implementation to simultaneously measure the optical proprieties of deep tissue as well as the blood flow. The system consists of three long coherence length lasers at different wavelengths in the near-infrared, eight single-photon detectors, and a correlator board. With this approach, we collect both light intensity and DCS data at multiple distances and multiple wavelengths, which provide unique information to fit for all the parameters of interest: scattering, blood flow, and hemoglobin concentration. We present the characterization of the system and its validation with phantom measurements.

Publisher Correction: Shedding light on the neonatal brain: probing cerebral hemodynamics by diffuse optical spectroscopic methods.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Prolonged monitoring of cerebral blood flow and autoregulation with diffuse correlation spectroscopy in neurocritical care patients.

Monitoring of cerebral blood flow (CBF) and autoregulation are essential components of neurocritical care, but continuous noninvasive methods for CBF monitoring are lacking. Diffuse correlation spectroscopy (DCS) is a noninvasive diffuse optical modality that measures a CBF index ( CBF i ) in the cortex microvasculature by monitoring the rapid fluctuations of near-infrared light diffusing through moving red blood cells. We tested the feasibility of monitoring CBF i with DCS in at-risk patients in the Neurosciences Intensive Care Unit. DCS data were acquired continuously for up to 20 h in six patients with aneurysmal subarachnoid hemorrhage, as permitted by clinical care. Mean arterial blood pressure was recorded synchronously, allowing us to derive autoregulation curves and to compute an autoregulation index. The autoregulation curves suggest disrupted cerebral autoregulation in most patients, with the severity of disruption and the limits of preserved autoregulation varying between subjects. Our findings suggest the potential of the DCS modality for noninvasive, long-term monitoring of cerebral perfusion, and autoregulation.

Pre-clinical longitudinal monitoring of hemodynamic response to anti-vascular chemotherapy by hybrid diffuse optics.

The longitudinal effect of an anti-vascular endothelial growth factor receptor 2 (VEGFR-2) antibody (DC 101) therapy on a xenografted renal cell carcinoma (RCC) mouse model was monitored using hybrid diffuse optics. Two groups of immunosuppressed male nude mice (seven treated, seven controls) were measured. Tumor microvascular blood flow, total hemoglobin concentration and blood oxygenation were investigated as potential biomarkers for the monitoring of the therapy effect twice a week and were related to the final treatment outcome. These hemodynamic biomarkers have shown a clear differentiation between two groups by day four. Moreover, we have observed that pre-treatment values and early changes in hemodynamics are highly correlated with the therapeutic outcome demonstrating the potential of diffuse optics to predict the therapy response at an early time point.

Combined multi-distance frequency domain and diffuse correlation spectroscopy system with simultaneous data acquisition and real-time analysis.

Frequency domain near infrared spectroscopy (FD-NIRS) and diffuse correlation spectroscopy (DCS) have emerged as synergistic techniques for the non-invasive assessment of tissue health. Combining FD-NIRS oximetry with DCS measures of blood flow, the tissue oxygen metabolic rate can be quantified, a parameter more closely linked to underlying physiology and pathology than either NIRS or DCS estimates alone. Here we describe the first commercially available integrated instrument, called the "MetaOx", designed to enable simultaneous FD-NIRS and DCS measurements at rates of 10 + Hz, and offering real-time data evaluation. We show simultaneously acquired characterization data demonstrating performance equivalent to individual devices and sample in vivo measurements of pulsation resolved blood flow, forearm occlusion hemodynamic changes and muscle oxygen metabolic rate monitoring during stationary bike exercise.

Shedding light on the neonatal brain: probing cerebral hemodynamics by diffuse optical spectroscopic methods.

Investigating the cerebral physiology of healthy term newborns' brains is important for better understanding perinatal brain injuries, of which the most common etiologies are hypoxia and ischemia. Hence, cerebral blood flow and cerebral oxygenation are important biomarkers of brain health. In this study, we employed a hybrid diffuse optical system consisting of diffuse correlation spectroscopy (DCS) and frequency-domain near infrared spectroscopy (FDNIRS) to measure hemoglobin concentration, oxygen saturation, and indices of cerebral blood flow and metabolism. We measured 30 term infants to assess the optical and physiological characteristics of the healthy neonatal brain in the frontal, temporal, and parietal lobes. We observed higher metabolism in the right hemisphere compared to the left and a positive correlation between gestational age and the level of cerebral hemoglobin concentration, blood volume, and oxygen saturation. Moreover, we observed higher cerebral blood flow and lower oxygen saturation in females compared to males. The delayed maturation in males and the sexual dimorphism in cerebral hemodynamics may explain why males are more vulnerable to perinatal brain injuries than females.

Scanning, non-contact, hybrid broadband diffuse optical spectroscopy and diffuse correlation spectroscopy system.

A scanning system for small animal imaging using non-contact, hybrid broadband diffuse optical spectroscopy (ncDOS) and diffuse correlation spectroscopy (ncDCS) is presented. The ncDOS uses a two-dimensional spectrophotometer retrieving broadband (610-900 nm) spectral information from up to fifty-seven source-detector distances between 2 and 5 mm. The ncDCS data is simultaneously acquired from four source-detector pairs. The sample is scanned in two dimensions while tracking variations in height. The system has been validated with liquid phantoms, demonstrated in vivo on a human fingertip during an arm cuff occlusion and on a group of mice with xenoimplanted renal cell carcinoma.

Establishing the diffuse correlation spectroscopy signal relationship with blood flow.

Diffuse correlation spectroscopy (DCS) measurements of blood flow rely on the sensitivity of the temporal autocorrelation function of diffusively scattered light to red blood cell (RBC) mean square displacement (MSD). For RBCs flowing with convective velocity [Formula: see text], the autocorrelation is expected to decay exponentially with [Formula: see text], where [Formula: see text] is the delay time. RBCs also experience shear-induced diffusion with a diffusion coefficient [Formula: see text] and an MSD of [Formula: see text]. Surprisingly, experimental data primarily reflect diffusive behavior. To provide quantitative estimates of the relative contributions of convective and diffusive movements, we performed Monte Carlo simulations of light scattering through tissue of varying vessel densities. We assumed laminar vessel flow profiles and accounted for shear-induced diffusion effects. In agreement with experimental data, we found that diffusive motion dominates the correlation decay for typical DCS measurement parameters. Furthermore, our model offers a quantitative relationship between the RBC diffusion coefficient and absolute tissue blood flow. We thus offer, for the first time, theoretical support for the empirically accepted ability of the DCS blood flow index ([Formula: see text]) to quantify tissue perfusion. We find [Formula: see text] to be linearly proportional to blood flow, but with a proportionality modulated by the hemoglobin concentration and the average blood vessel diameter.

Diffuse Optical Characterization of the Healthy Human Thyroid Tissue and Two Pathological Case Studies.

The in vivo optical and hemodynamic properties of the healthy (n = 22) and pathological (n = 2) human thyroid tissue were measured non-invasively using a custom time-resolved spectroscopy (TRS) and diffuse correlation spectroscopy (DCS) system. Medical ultrasound was used to guide the placement of the hand-held hybrid optical probe. TRS measured the absorption and reduced scattering coefficients (µa, µs') at three wavelengths (690, 785 and 830 nm) to derive total hemoglobin concentration (THC) and oxygen saturation (StO2). DCS measured the microvascular blood flow index (BFI). Their dependencies on physiological and clinical parameters and positions along the thyroid were investigated and compared to the surrounding sternocleidomastoid muscle. The THC in the thyroid ranged from 131.9 µM to 144.8 µM, showing a 25-44% increase compared to the surrounding sternocleidomastoid muscle tissue. The blood flow was significantly higher in the thyroid (BFIthyroid = 16.0 × 10-9 cm2/s) compared to the muscle (BFImuscle = 7.8 × 10-9 cm2/s), while StO2 showed a small (StO2, muscle = 63.8% to StO2, thyroid = 68.4%), yet significant difference. Two case studies with thyroid nodules underwent the same measurement protocol prior to thyroidectomy. Their THC and BFI reached values around 226.5 µM and 62.8 × 10-9 cm2/s respectively showing a clear contrast to the nodule-free thyroid tissue as well as the general population. The initial characterization of the healthy and pathologic human thyroid tissue lays the ground work for the future investigation on the use of diffuse optics in thyroid cancer screening.

Chemotherapeutic drug-specific alteration of microvascular blood flow in murine breast cancer as measured by diffuse correlation spectroscopy.

The non-invasive, in vivo measurement of microvascular blood flow has the potential to enhance breast cancer therapy monitoring. Here, longitudinal blood flow of 4T1 murine breast cancer (N=125) under chemotherapy was quantified with diffuse correlation spectroscopy based on layer models. Six different treatment regimens involving doxorubicin, cyclophosphamide, and paclitaxel at clinically relevant doses were investigated. Treatments with cyclophosphamide increased blood flow as early as 3 days after administration, whereas paclitaxel induced a transient blood flow decrease at 1 day after administration. Early blood flow changes correlated strongly with the treatment outcome and distinguished treated from untreated mice individually for effective treatments.

In Vivo, Non-Invasive Characterization of Human Bone by Hybrid Broadband (600-1200 nm) Diffuse Optical and Correlation Spectroscopies.

Non-invasive in vivo diffuse optical characterization of human bone opens a new possibility of diagnosing bone related pathologies. We present an in vivo characterization performed on seventeen healthy subjects at six different superficial bone locations: radius distal, radius proximal, ulna distal, ulna proximal, trochanter and calcaneus. A tailored diffuse optical protocol for high penetration depth combined with the rather superficial nature of considered tissues ensured the effective probing of the bone tissue. Measurements were performed using a broadband system for Time-Resolved Diffuse Optical Spectroscopy (TRS) to assess mean absorption and reduced scattering spectra in the 600-1200 nm range and Diffuse Correlation Spectroscopy (DCS) to monitor microvascular blood flow. Significant variations among tissue constituents were found between different locations; with radius distal rich of collagen, suggesting it as a prominent location for bone related measurements, and calcaneus bone having highest blood flow among the body locations being considered. By using TRS and DCS together, we are able to probe the perfusion and oxygen consumption of the tissue without any contrast agents. Therefore, we predict that these methods will be able to evaluate the impairment of the oxygen metabolism of the bone at the point-of-care.

Multidistance diffuse correlation spectroscopy for simultaneous estimation of blood flow index and optical properties.

Traditionally, diffuse correlation spectroscopy (DCS) measures microvascular blood flow by fitting a physical model to the measurement of the intensity autocorrelation function from a single source-detector pair. This analysis relies on the accurate knowledge of the optical properties, absorption, and reduced scattering coefficients of the medium. Therefore, DCS is often deployed together with diffuse optical spectroscopy. We present an algorithm that employs multidistance DCS (MD-DCS) for simultaneous measurement of bloodflow index, as well as an estimate of the optical properties of the tissue. The algorithm has been validated through noise-free and noise-added simulated data and phantom measurements. A longitudinal in vivo measurement ofa mouse tumor is also shown. MD-DCS is introduced as a stand-alone system for small source-detector separations (<2 cm) for noninvasive measurement of microvascular blood flow.

Noninvasive characterization of the healthy human manubrium using diffuse optical spectroscopies.

The abnormal, uncontrolled production of blood cells in the bone marrow causes hematological malignancies which are common and tend to have a poor prognosis. These types of cancers may alter the hemodynamics of bone marrow. Therefore, noninvasive methods that measure the hemodynamics in the bone marrow have a potential impact on the earlier diagnosis, more accurate prognosis, and in treatment monitoring. In adults, the manubrium is one of the few sites of bone marrow that is rich in hematopoietic tissue and is also relatively superficial and accessible. To this end we have combined time resolved spectroscopy and diffuse correlation spectroscopy to evaluate the feasibility of the noninvasive measurement of the hemodynamics properties of the healthy manubrium in 32 subjects. The distribution of the optical properties (absorption and scattering) and physiological properties (hemoglobin concentration, oxygen saturation and blood flow index) of this tissue are presented as the first step toward investigating its pathology.

Pulsatile and steady-state hemodynamics of the human patella bone by diffuse optical spectroscopy.

The cardiac cycle related pulsatile behavior of the absorption and scattering coefficients of diffuse light and the corresponding alterations in hemoglobin concentrations in the human patella was studied. The pulsations in scattering is considerably smaller than absorption. The difference in amplitude of absorption coefficient pulsations for different wavelengths was translated to pulsations in oxygenated and deoxygenated hemoglobin, which leads to strong pulsations in the total hemoglobin concentration and oxygen saturation. The physiological origin of the observed signals was confirmed by applying a thigh-cuff. Moreover, we have investigated the optical and physiological properties of the patella bone and their changes in response to arterial cuff occlusion.