We developed and evaluated a low-cost, miniaturized, and user-friendly speckle contrast diffuse correlation tomography (scDCT) device for noncontact, fast, high-density, and depth-sensitive imaging of CBF distribution in the brain. The new low-cost portable scDCT device was evaluated against an established large scDCT system using head-simulating phantoms with known optical properties and the mouse with transient ligations of common carotid arteries. Results taken from the two scDCT systems were highly consistent. The low-cost miniaturized scDCT has the potential to be commercialized as an affordable, portable, and ergonomic brain monitoring tool for neuroscience research in numerous academic and industrial laboratories.
We investigated the impact of laser coherence length on reconstructed flow contrast images with our innovative speckle contrast diffuse correlation tomography (scDCT) device. We tested three lasers with varied coherence lengths: >10 meters, ~3.3 millimeters, and ~390 micrometers. Lasers with coherence lengths larger than millimeters yielded good-quality flow images with higher signal-to-noise ratios (SNR) and less image distortion. We concluded that scDCT measurements do not require excessively long coherence lasers with high costs.
KEYWORDS: Speckle, Laser speckle contrast imaging, Windows, Brain mapping, Simulation of CCA and DLA aggregates, Brain, 3D modeling, Spatial resolution, Tissues, Neurophotonics
SignificanceFrequent assessment of cerebral blood flow (CBF) is crucial for the diagnosis and management of cerebral vascular diseases. In contrast to large and expensive imaging modalities, such as nuclear medicine and magnetic resonance imaging, optical imaging techniques are portable and inexpensive tools for continuous measurements of cerebral hemodynamics. The recent development of an innovative noncontact speckle contrast diffuse correlation tomography (scDCT) enables three-dimensional (3D) imaging of CBF distributions. However, scDCT requires complex and time-consuming 3D reconstruction, which limits its ability to achieve high spatial resolution without sacrificing temporal resolution and computational efficiency.AimWe investigate a new diffuse speckle contrast topography (DSCT) method with parallel computation for analyzing scDCT data to achieve fast and high-density two-dimensional (2D) mapping of CBF distributions at different depths without the need for 3D reconstruction.ApproachA new moving window method was adapted to improve the sampling rate of DSCT. A fast computation method utilizing MATLAB functions in the Image Processing Toolbox™ and Parallel Computing Toolbox™ was developed to rapidly generate high-density CBF maps. The new DSCT method was tested for spatial resolution and depth sensitivity in head-simulating layered phantoms and in-vivo rodent models.ResultsDSCT enables 2D mapping of the particle flow in the phantom at different depths through the top layer with varied thicknesses. Both DSCT and scDCT enable the detection of global and regional CBF changes in deep brains of adult rats. However, DSCT achieves fast and high-density 2D mapping of CBF distributions at different depths without the need for complex and time-consuming 3D reconstruction.ConclusionsThe depth-sensitive DSCT method has the potential to be used as a noninvasive, noncontact, fast, high resolution, portable, and inexpensive brain imager for basic neuroscience research in small animal models and for translational studies in human neonates.
KEYWORDS: Brain, Ischemia, Simulation of CCA and DLA aggregates, Windows, Speckle, 3D image reconstruction, Sampling rates, Tissues, Reconstruction algorithms, Neuroimaging
SignificanceLow-frequency oscillations (LFOs) (<0.1 Hz) with respect to cerebral blood flow (CBF) have shown promise as an indicator of altered neurologic activity in the abnormal brain. Portable optical instruments have evolved to offer a noninvasive alternative for continuous CBF monitoring at the bedside compared with many large neuroimaging modalities. However, their utilization for acquiring LFOs of CBF has only been studied to a limited extent.AimWe aim to optimize an innovative speckle contrast diffuse correlation tomography (scDCT) system for the detection of LFOs within CBF variations.ApproachThe scDCT was optimized to achieve a higher sampling rate and a faster image reconstruction using a moving window 3D reconstruction algorithm with parallel computation. Power spectral density (PSD) analysis was performed to investigate altered LFOs during transient global cerebral ischemia in neonatal piglets.ResultsTransient global cerebral ischemia resulted in reductions in both CBF and PSD compared with their baseline values.ConclusionsSpontaneous LFOs, combined with CBF, provide a more comprehensive assay with the potential to clarify pathological mechanisms involved in brain injury. These results support scDCT’s inclusion and application in the growing area of LFO analysis and demonstrate its inherent advantage for neurological studies in preclinical and clinical settings, such as neonatal intensive care units.
An innovative camera-based speckle contrast diffuse correlation tomography (scDCT) technology has been developed recently, which enables noncontact, noninvasive, high-density, 3D imaging of cerebral blood flow (CBF) distributions. This study demonstrated the capability and safety of scDCT technique for imaging of CBF distributions in a neonatal piglet model of transient ischemic stroke. Moreover, power spectral density analyses of low-frequency oscillations (LFOs) and the network connections over the brain were assessed before and after the induction of acute ischemic stroke. The stroke resulted in a substantial decrease in CBF, attenuations in resting-state LFOs, and functional connectivity disruptions in motor and somatosensory cortices.
Laser speckle contrast imaging (LSCI) illuminates continuous-wave (CW) laser light on tissue surface. We assembled an integrated LSCI system combining a CW laser at 785 nm and a picosecond pulsed laser at 775 nm. A CMOS camera collected images from mouse head with intact skull. The pulsed laser with engineered diffuser captured more details of brain vessels compared to the CW laser with glass diffusers. The consecutive ligations of left and right common carotid arteries resulted in significant CBF reductions. This research lays the ground to develop multimodal imaging systems integrating LSCI and other imaging techniques with shared pulse illuminations.
KEYWORDS: Ischemia, Optical sensors, Simulation of CCA and DLA aggregates, Semiconductor lasers, Detector arrays, Spectroscopy, Speckle, Neuroscience, Laser tissue interaction, Head
We report an innovative, wearable, multiscale diffuse speckle contrast flowmetry (DSCF) probe for continuous transcranial imaging of cerebral blood flow (CBF) in animal s. Significant reductions in CBF during transient ligation of bilateral common carotid arteries were detected by DSCF (-35±13% in two mice and -59% in a piglet), meeting clinical expectations. Results from DSCF and an established CBF measurement device, diffuse correlation spectroscopy, were consistent and significantly correlated. With further optimization and validation in animals and humans, we expect to ultimately offer a unique, noninvasive, low-cost, and fast brain imaging tool for basic neuroscience research and clinical applications.
We present an innovative, wearable, fiber-free, near-infrared diffuse speckle contrast flowmetry (DSCF) probe that is fixed on the skull for continuous monitoring of cerebral blood flow (CBF) variations in mice during anesthesia, awake, and freely behaving. Results show a small surge when the animal waked up, a mild decrease after the isoflurane washed off, a 37 ± 9% increase during 10%CO2 inhalation (n = 3), and mild elevations during grooming and walking. These CBF variations are consistent with clinical observations when recovery from anesthesia and impacts by isoflurane, hypercapnia (CO2), and activity-induced cortical excitations.
Intraventricular hemorrhage (IVH) is the most common neurological complication of prematurity. IVH is a bleeding inside or around ventricles, spaces in the brain containing the cerebrospinal fluid, which occurs as a result of the fragility and immaturity of blood vessels in premature brains. Severe IVH disrupts development of structural and functional connectivity networks, leading to impairments of cerebral development and neurologic deficits. Preterm infants with IVH are prone to alterations in cerebral blood flow (CBF) and associated spontaneous low-frequency fluctuations. However, there are no established noninvasive imaging methods for continuous monitoring of CBF alterations at the bedside in neonatal intensive care units. An innovative CCD/CMOS based speckle contrast diffuse correlation tomography (scDCT) technology has been recently developed in our laboratory, which enables noncontact, noninvasive, and high-density 3D imaging of CBF distributions in deep brain cortex. In the present study, the capability of scDCT technique for noncontact 3D imaging of CBF distributions in a neonatal piglet model of IVH was demonstrated. Moreover, power spectral density analyses of scDCT data were performed to assess alterations in spontaneous low frequency fluctuations in the resting brain, before and after inducing IVH. IVH resulted in a CBF decrease in deep brain cortex. Resting-state spontaneous low-frequency fluctuations after IVH showed attenuations in all frequencies (0.009– 0.08 Hz) compared to the baseline before IVH. In conclusion, scDCT is capable of detecting brain hemodynamic disruptions (reduction in CBF and attenuation in spontaneous low-frequency fluctuations) after IVH, which might be useful for instant management of IVH and associated complications.
Significance: There is an essential need to develop wearable multimodality technologies that can continuously measure both blood flow and oxygenation in deep tissues to investigate and manage various vascular/cellular diseases.
Aim: To develop a wearable dual-wavelength diffuse speckle contrast flow oximetry (DSCFO) for simultaneous measurements of blood flow and oxygenation variations in deep tissues.
Approach: A wearable fiber-free DSCFO probe was fabricated using 3D printing to confine two small near-infrared laser diodes and a tiny CMOS camera in positions for DSCFO measurements. The spatial diffuse speckle contrast and light intensity measurements at the two different wavelengths enable quantification of tissue blood flow and oxygenation, respectively. The DSCFO was first calibrated using tissue phantoms and then tested in adult forearms during artery cuff occlusion.
Results: Phantom tests determined the largest effective source–detector distance (15 mm) and optimal camera exposure time (10 ms) and verified the accuracy of DSCFO in measuring absorption coefficient variations. The DSCFO detected substantial changes in forearm blood flow and oxygenation resulting from the artery occlusion, which meet physiological expectations and are consistent with previous study results.
Conclusions: The wearable DSCFO may be used for continuous and simultaneous monitoring of blood flow and oxygenation variations in freely behaving subjects.
A noncontact electron multiplying charge-coupled-device (EMCCD)-based speckle contrast diffuse correlation tomography (scDCT) technology has been recently developed in our laboratory, allowing for noninvasive three-dimensional measurement of tissue blood flow distributions. One major remaining constraint in the scDCT is the assumption of a semi-infinite tissue volume with a flat surface, which affects the image reconstruction accuracy for tissues with irregular geometries. An advanced photometric stereo technique (PST) was integrated into the scDCT system to obtain the surface geometry in real time for image reconstruction. Computer simulations demonstrated that a priori knowledge of tissue surface geometry is crucial for precisely reconstructing the anomaly with blood flow contrast. Importantly, the innovative integration design with one single-EMCCD camera for both PST and scDCT data collection obviates the need for offline alignment of sources and detectors on the tissue boundary. The in vivo imaging capability of the updated scDCT is demonstrated by imaging dynamic changes in forearm blood flow distribution during a cuff-occlusion procedure. The feasibility and safety in clinical use are evidenced by intraoperative imaging of mastectomy skin flaps and comparison with fluorescence angiography.
This study used a hybrid near-infrared diffuse optical instrument to monitor tumor hemodynamic responses to chemoradiation therapy for early prediction of treatment outcomes in patients with head and neck cancer. Forty-seven patients were measured once per week to evaluate the hemodynamic status of clinically involved cervical lymph nodes as surrogates for the primary tumor response. Patients were classified into two groups: complete response (CR) (n=29) and incomplete response (IR) (n=18). Tumor hemodynamic responses were found to be associated with clinical outcomes (CR/IR), wherein the associations differed depending on human papillomavirus (HPV-16) status. In HPV-16 positive patients, significantly lower levels in tumor oxygenated hemoglobin concentration ([HbO2]) at weeks 1 to 3, total hemoglobin concentration at week 3, and blood oxygen saturation (StO2) at week 3 were found in the IR group. In HPV-16 negative patients, significantly higher levels in tumor blood flow index and reduced scattering coefficient (μs′) at week 3 were observed in the IR group. These hemodynamic parameters exhibited significantly high accuracy for early prediction of clinical outcomes, within the first three weeks of therapy, with the areas under the receiver operating characteristic curves (AUCs) ranging from 0.83 to 0.96.
We report a low-cost compact diffuse speckle contrast flowmeter (DSCF) consisting of a small laser diode and a bare charge-coupled-device (CCD) chip, which can be used for contact measurements of blood flow variations in relatively deep tissues (up to ∼8 mm). Measurements of large flow variations by the contact DSCF probe are compared to a noncontact CCD-based diffuse speckle contrast spectroscopy and a standard contact diffuse correlation spectroscopy in tissue phantoms and a human forearm. Bland–Altman analysis shows no significant bias with good limits of agreement among these measurements: 96.5%±2.2% (94.4% to 100.0%) in phantom experiments and 92.8% in the forearm test. The relatively lower limit of agreement observed in the in vivo measurements (92.8%) is likely due to heterogeneous reactive responses of blood flow in different regions/volumes of the forearm tissues measured by different probes. The low-cost compact DSCF device holds great potential to be broadly used for continuous and longitudinal monitoring of blood flow alterations in ischemic/hypoxic tissues, which are usually associated with various vascular diseases.
Head and neck cancer accounts for 3 to 5% of all cancers in the United States. Primary or salvage surgeries are extensive and often lead to major head and neck defects that require complex reconstructions with local, regional, or free tissue transfer flaps. Knowledge of tissue blood flow (BF) changes after free tissue transfer may enable surgeons to predict the failure of flap thrombosis at an early stage. This study used our recently developed noncontact diffuse correlation spectroscopy to monitor dynamic BF changes in free flaps without getting in contact with the targeted tissue. Eight free flaps were elevated in patients with head and neck cancer; one of the flaps failed. Multiple BF measurements probing the transferred tissue were performed during and post the surgical operation. Postoperative BF values were normalized to the intraoperative baselines (assigning '1') for the calculation of relative BF change (rBF). The rBF changes over the seven successful flaps were 1.89 ± 0.15, 2.26 ± 0.13, and 2.43 ± 0.13 (mean ± standard error) respectively on postoperative days 2, 4, and 7. These postoperative values were significantly higher than the intraoperative baseline values (p < 0.001), indicating a gradual recovery of flap vascularity after the tissue transfer. By contrast, rBF changes observed from the unsuccessful flap were 1.14 and 1.34 respectively on postoperative days 2 and 4, indicating a less flow recovery. Measurement of BF recovery after flap anastomosis holds the potential to act early to salvage ischemic flaps.
Radiation therapy is a principal modality for head and neck cancers and its efficacy depends on tumor hemodynamics. Our laboratory developed a hybrid diffuse optical instrument allowing for simultaneous measurements of tumor blood flow and oxygenation. In this study, the clinically involved cervical lymph node was monitored by the hybrid instrument once a week over the treatment period of seven weeks. Based on treatment outcomes within one year, patients were classified into a complete response group (CR) and an incomplete response group (IR) with remote metastasis and/or local recurrence. A linear mixed models was used to compare tumor hemodynamic responses to the treatment between the two groups. Interestingly, we found that human papilloma virus (HPV-16) status largely affected tumor hemodynamic responses. For HPV-16 negative tumors, significant differences in blood flow index (BFI, p = 0.007) and reduced scattering coefficient (μs’, p = 0.0005) were observed between the two groups; IR tumors exhibited higher μs’ values and a continuous increase in BFI over the treatment period. For HPV-16 positive tumors, oxygenated hemoglobin concentration ([HbO2]) and blood oxygen saturation (StO2) were significant different (p = 0.003 and 0.01, respectively); IR group showed lower [HbO2] and StO2. Our results imply HPV-16 negative tumors with higher density of vasculature (μs’) and higher blood flow show poor responses to radiotherapy and HPV-16 positive tumors with lower tissue oxygenation level (lower StO2 and [HbO2]) exhibit poor treatment outcomes. Our diffuse optical measurements show the great potential for early prediction of radiotherapy in head and neck cancers.
Occlusion calibrations and gating techniques have been recently applied by our laboratory for continuous and absolute diffuse optical measurements of forearm muscle hemodynamics during handgrip exercises. The translation of these techniques from the forearm to the lower limb is the goal of this study as various diseases preferentially affect muscles in the lower extremity. This study adapted a hybrid near-infrared spectroscopy and diffuse correlation spectroscopy system with a gating algorithm to continuously quantify hemodynamic responses of medial gastrocnemius during plantar flexion exercises in 10 healthy subjects. The outcomes from optical measurement include oxy-, deoxy-, and total hemoglobin concentrations, blood oxygen saturation, and relative changes in blood flow (rBF) and oxygen consumption rate (rV˙O2). We calibrated rBF and rV˙O2 profiles with absolute baseline values of BF and V˙O2 obtained by venous and arterial occlusions, respectively. Results from this investigation were comparable to values from similar studies. Additionally, significant correlation was observed between resting local muscle BF measured by the optical technique and whole limb BF measured concurrently by a strain gauge venous plethysmography. The extensive hemodynamic and metabolic profiles during exercise will allow for future comparison studies to investigate the diagnostic value of hybrid technologies in muscles affected by disease.
Our first step to adapt our recently developed noncontact diffuse correlation tomography (ncDCT) system for three-dimensional (3-D) imaging of blood flow distribution in human breast tumors is reported. A commercial 3-D camera was used to obtain breast surface geometry, which was then converted to a solid volume mesh. An ncDCT probe scanned over a region of interest on the mesh surface and the measured boundary data were combined with a finite element framework for 3-D image reconstruction of blood flow distribution. This technique was tested in computer simulations and in vivo human breasts with low-grade carcinoma. Results from computer simulations suggest that relatively high accuracy can be achieved when the entire tumor is within the sensitive region of diffuse light. Image reconstruction with a priori knowledge of the tumor volume and location can significantly improve the accuracy in recovery of tumor blood flow contrasts. In vivo imaging results from two breast carcinomas show higher average blood flow contrasts (5.9- and 10.9-fold) in the tumor regions compared to the surrounding tissues, which are comparable with previous findings using diffuse correlation spectroscopy. The ncDCT system has the potential to image blood flow distributions in soft and vulnerable tissues without distorting tissue hemodynamics.
Knowledge of tissue blood flow (BF) changes after free tissue transfer may enable surgeons to predict the failure of flap thrombosis at an early stage. This study used our recently developed noncontact diffuse correlation spectroscopy to monitor dynamic BF changes in free flaps without getting in contact with the targeted tissue. Eight free flaps were elevated in patients with head and neck cancer; one of the flaps failed. Multiple BF measurements probing the transferred tissue were performed during and post the surgical operation. Postoperative BF values were normalized to the intraoperative baselines (assigning “1”) for the calculation of relative BF change (rBF). The rBF changes over the seven successful flaps were 1.89±0.15, 2.26±0.13, and 2.43±0.13 (mean±standard error), respectively, on postoperative days 2, 4, and 7. These postoperative values were significantly higher than the intraoperative baseline values (p<0.001), indicating a gradual recovery of flap vascularity after the tissue transfer. By contrast, rBF changes observed from the unsuccessful flaps were 1.14 and 1.34, respectively, on postoperative days 2 and 4, indicating less flow recovery. Measurement of BF recovery after flap anastomosis holds the potential to act early to salvage ischemic flaps.
Significant drops in arterial blood pressure and cerebral hemodynamics have been previously observed during vasovagal syncope (VVS). Continuous and simultaneous monitoring of these physiological variables during VVS is rare, but critical for determining which variable is the most sensitive parameter to predict VVS. The present study used a novel custom-designed diffuse correlation spectroscopy flow-oximeter and a finger plethysmograph to simultaneously monitor relative changes of cerebral blood flow (rCBF), cerebral oxygenation (i.e., oxygenated/deoxygenated/total hemoglobin concentration: r[HbO 2 ]/r[Hb]/rTHC ), and mean arterial pressure (rMAP) during 70 deg head-up tilt (HUT) in 14 healthy adults. Six subjects developed presyncope during HUT. Two-stage physiological responses during HUT were observed in the presyncopal group: slow and small changes in measured variables (i.e., Stage I), followed by rapid and dramatic decreases in rMAP, rCBF, r[HbO 2 ] , and rTHC (i.e., Stage II). Compared to other physiological variables, rCBF reached its breakpoint between the two stages earliest and had the largest decrease (76±8% ) during presyncope. Our results suggest that rCBF has the best sensitivity for the assessment of VVS. Most importantly, a threshold of ∼50% rCBF decline completely separated the subjects from those without presyncope, suggesting its potential for predicting VVS.
Technologies currently available for the monitoring of electrical stimulation (ES) in promoting blood circulation and tissue oxygenation are limited. This study integrated a muscle stimulator with a diffuse correlation spectroscopy (DCS) flow-oximeter to noninvasively quantify muscle blood flow and oxygenation responses during ES. Ten healthy subjects were tested using the integrated system. The muscle stimulator delivered biphasic electrical current to right leg quadriceps muscle, and a custom-made DCS flow-oximeter was used for simultaneous measurements of muscle blood flow and oxygenation in both legs. To minimize motion artifact of muscle fibers during ES, a novel gating algorithm was developed for data acquisition at the time when the muscle was relaxed. ES at 2, 10, and 50 Hz were applied for 20 min on each subject in three days sequentially. Results demonstrate that the 20-min ES at all frequencies promoted muscle blood flow significantly. However, only the ES at 10 Hz resulted in significant and persistent increases in oxy-hemoglobin concentration during and post ES. This pilot study supports the application of the integrated system to quantify tissue hemodynamic improvements for the optimization of ES treatment in patients suffering from diseases caused by poor blood circulation and low tissue oxygenation (e.g., pressure ulcer).
Peripheral artery disease (PAD) is a common condition with high morbidity. While measurement of tissue oxygen saturation (S t O 2 ) has been demonstrated, this is the first study to assess both S t O 2 and relative blood flow (rBF) in the extremities of PAD patients. Diffuse optics is employed to measure hemodynamic response to treadmill and pedal exercises in 31 healthy controls and 26 patients. For S t O 2 , mild and moderate/severe PAD groups show pronounced differences compared with controls. Pre-exercise mean S t O 2 is lower in PAD groups by 9.3% to 10.6% compared with means of 63.5% to 66.2% in controls. For pedal, relative rate of return of S t O 2 to baseline is more rapid in controls (p<0.05 ). Patterns of rBF also differ among groups. After both exercises, rBF tend to occur at depressed levels among severe PAD patients compared with healthy (p<0.05 ); post-treadmill, rBF tend to occur at elevated levels among healthy compared with severe PAD patients (p<0.05 ). Additionally, relative rate of return to baseline S t O 2 is more rapid among subjects with reduced levels of depression in rBF (p=0.041 ), even after adjustment for ankle brachial index. This suggests a physiologic connection between rBF and oxygenation that can be measured using diffuse optics, and potentially employed as an evaluative tool in further studies.
The dual-wavelength diffuse correlation spectroscopy (DCS) flow-oximeter is an emerging technique enabling simultaneous measurements of blood flow and blood oxygenation changes in deep tissues. High signal-to-noise ratio (SNR) is crucial when applying DCS technologies in the study of human tissues where the detected signals are usually very weak. In this study, single-mode, few-mode, and multimode fibers are compared to explore the possibility of improving the SNR of DCS flow-oximeter measurements. Experiments on liquid phantom solutions and in vivo muscle tissues show only slight improvements in flow measurements when using the few-mode fiber compared with using the single-mode fiber. However, light intensities detected by the few-mode and multimode fibers are increased, leading to significant SNR improvements in detections of phantom optical property and tissue blood oxygenation. The outcomes from this study provide useful guidance for the selection of optical fibers to improve DCS flow-oximeter measurements.
This study investigates a method using novel hybrid diffuse optical spectroscopies [near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS)] to obtain continuous, noninvasive measurement of absolute blood flow (BF), blood oxygenation, and oxygen consumption rate (O2) in exercising skeletal muscle. Healthy subjects (n = 9) performed a handgrip exercise to increase BF and O2 in forearm flexor muscles, while a hybrid optical probe on the skin surface directly monitored oxy-, deoxy-, and total hemoglobin concentrations ([HbO2], [Hb], and THC), tissue oxygen saturation (StO2), relative BF (rBF), and relative oxygen consumption rate (rO2). The rBF and rO2 signals were calibrated with absolute baseline BF and O2 obtained through venous and arterial occlusions, respectively. Known problems with muscle-fiber motion artifacts in optical measurements during exercise were mitigated using a novel gating algorithm that determined muscle contraction status based on control signals from a dynamometer. Results were consistent with previous findings in the literature. This study supports the application of NIRS/DCS technology to quantitatively evaluate hemodynamic and metabolic parameters in exercising skeletal muscle and holds promise for improving diagnosis and treatment evaluation for patients suffering from diseases affecting skeletal muscle and advancing fundamental understanding of muscle and exercise physiology.
A novel near-infrared (NIR) diffuse correlation spectroscopy (DCS) for tumor blood flow measurement is introduced in this review paper. DCS measures speckle fluctuations of NIR diffuse light in tissue, which are sensitive to the motions of red blood cells. DCS offers several attractive new features for tumor blood flow measurement such as noninvasiveness, portability, high temporal resolution, and relatively large penetration depth. DCS technology has been utilized for continuous measurement of tumor blood flow before, during, and after cancer therapies. In those pilot investigations, DCS hemodynamic measurements add important new variables into the mix for differentiation of benign from malignant tumors and for prediction of treatment outcomes. It is envisaged that with more clinical applications in large patient populations, DCS might emerge as an important method of choice for bedside management of cancer therapy, and it will certainly provide important new information about cancer physiology that may be of use in diagnosis.
A noncontact diffuse correlation spectroscopy (DCS) probe has been developed using two separated optical paths for the source and detector. This unique design avoids the interference between the source and detector and allows large source-detector separations for deep tissue blood flow measurements. The noncontact probe has been calibrated against a contact probe in a tissue-like phantom solution and human muscle tissues; flow changes concurrently measured by the two probes are highly correlated in both phantom (R2 = 0.89, p<10−5) and real-tissue (R2 = 0.77, p<10−5, n = 9) tests. The noncontact DCS holds promise for measuring blood flow in vulnerable (e.g., pressure ulcer) and soft (e.g., breast) tissues without distorting tissue hemodynamic properties.
Arterial revascularization in patients with peripheral arterial disease (PAD) reestablishes large arterial blood supply to the ischemic muscles in lower extremities via bypass grafts or percutaneous transluminal angioplasty (PTA). Currently no gold standard is available for assessment of revascularization effects in lower extremity muscles. This study tests a novel near-infrared diffuse correlation spectroscopy flow-oximeter for monitoring of blood flow and oxygenation changes in medial gastrocnemius (calf) muscles during arterial revascularization. Twelve limbs with PAD undergoing revascularization were measured using a sterilized fiber-optic probe taped on top of the calf muscle. The optical measurement demonstrated sensitivity to dynamic physiological events, such as arterial clamping/releasing during bypass graft and balloon inflation/deflation during PTA. Significant elevations in calf muscle blood flow were observed after revascularization in patients with bypass graft (+48.1 ± 17.5%) and patients with PTA (+43.2 ± 11.0%), whereas acute post-revascularization effects in muscle oxygenation were not evident. The decoupling of flow and oxygenation after revascularization emphasizes the need for simultaneous measurement of both parameters. The acute elevations/improvements in calf muscle blood flow were associated with significant improvements in symptoms and functions. In total, the investigation corroborates potential of the optical methods for objectively assessing the success of arterial revascularization.
Turgut Durduran, Chao Zhou, Erin Buckley, Meeri Kim, Guoqiang Yu, Regine Choe, J. William Gaynor, Thomas Spray, Suzanne Durning, Stefanie Mason, Lisa Montenegro, Susan Nicolson, Robert Zimmerman, Mary Putt, Jiongjiong Wang, Joel Greenberg, John Detre, Arjun Yodh, Daniel Licht
We employ a hybrid diffuse correlation spectroscopy (DCS) and near-infrared spectroscopy (NIRS) monitor for neonates with congenital heart disease (n=33). The NIRS-DCS device measured changes during hypercapnia of oxyhemoglobin, deoxyhemoglobin, and total hemoglobin concentrations; cerebral blood flow (rCBFDCS); and oxygen metabolism (rCMRO2). Concurrent measurements with arterial spin-labeled magnetic resonance imaging (rCBFASL-MRI, n=12) cross-validate rCBFDCS against rCBFASL-MRI, showing good agreement (R=0.7, p=0.01). The study demonstrates use of NIRS-DCS on a critically ill neonatal population, and the results indicate that the optical technology is a promising clinical method for monitoring this population.
We used a nonimpact inertial rotational model of a closed head injury in neonatal piglets to simulate the conditions following traumatic brain injury in infants. Diffuse optical techniques, including diffuse reflectance spectroscopy and diffuse correlation spectroscopy (DCS), were used to measure cerebral blood oxygenation and blood flow continuously and noninvasively before injury and up to 6 h after the injury. The DCS measurements of relative cerebral blood flow were validated against the fluorescent microsphere method. A strong linear correlation was observed between the two techniques (R=0.89, p<0.00001). Injury-induced cerebral hemodynamic changes were quantified, and significant changes were found in oxy- and deoxy-hemoglobin concentrations, total hemoglobin concentration, blood oxygen saturation, and cerebral blood flow after the injury. The diffuse optical measurements were robust and also correlated well with recordings of vital physiological parameters over the 6-h monitoring period, such as mean arterial blood pressure, arterial oxygen saturation, and heart rate. Finally, the diffuse optical techniques demonstrated sensitivity to dynamic physiological events, such as apnea, cardiac arrest, and hypertonic saline infusion. In total, the investigation corraborates potential of the optical methods for bedside monitoring of pediatric and adult human patients in the neurointensive care unit.
We combine diffuse optical spectroscopy (DOS) and diffuse correlation spectroscopy (DCS) to noninvasively monitor early hemodynamic response to neoadjuvant chemotherapy in a breast cancer patient. The potential for early treatment monitoring is demonstrated. Within the first week of treatment (day 7) DOS revealed significant changes in tumor/normal contrast compared to pretreatment (day 0) tissue concentrations of deoxyhemoglobin (rctHHbT/N=69±21%), oxyhemoglobin (rctO2HbT/N=73±25%), total hemoglobin (rctTHbT/N=72±17%), and lipid concentration (rctLipidT/N=116±13%). Similarly, DCS found significant changes in tumor/normal blood flow contrast (rBFT/N=75±7% on day 7 with respect to day 0). Our observations suggest the combination of DCS and DOS enhances treatment monitoring compared to either technique alone. The hybrid approach also enables construction of indices reflecting tissue metabolic rate of oxygen, which may provide new insights about therapy mechanisms.
This pilot study explores the potential of noninvasive diffuse correlation spectroscopy (DCS) and diffuse reflectance spectroscopy (DRS) for monitoring early relative blood flow (rBF), tissue oxygen saturation (StO2), and total hemoglobin concentration (THC) responses to chemo-radiation therapy in patients with head and neck tumors. rBF, StO2, and THC in superficial neck tumor nodes of eight patients are measured before and during the chemo-radiation therapy period. The weekly rBF, StO2, and THC kinetics exhibit different patterns for different individuals, including significant early blood flow changes during the first two weeks. Averaged blood flow increases (52.7±9.7)% in the first week and decreases (42.4±7.0)% in the second week. Averaged StO2 increases from (62.9±3.4)% baseline value to (70.4±3.2)% at the end of the second week, and averaged THC exhibits a continuous decrease from pretreatment value of (80.7±7.0) [µM] to (73.3±8.3) [µM] at the end of the second week and to (63.0±8.1) [µM] at the end of the fourth week of therapy. These preliminary results suggest daily diffuse-optics-based therapy monitoring is feasible during the first two weeks and may have clinical promise.
The aim is to evaluate the usefulness of optical blood flow measurements for predicting early tumor response to radiation therapy in patients with head and neck tumors. The results suggest a correlation between tumor blood flow changes with clinical outcome.
We have employed near-infrared optical methods to measure noninvasively the dynamics of muscle blood flow and oxygen saturation (StO2) during cuff occlusion and plantar flexion exercise. Relative muscle oxygen consumption (rVO2) was also computed from these data. Diffuse correlation spectroscopy provides information about blood flow, and diffuse reflectance spectroscopy provides information about blood oxygenation. Ten healthy subjects and one patient with peripheral arterial disease (PAD) were studied during 3-min arterial cuff occlusion of arm and leg, and during 1-min plantar flexion exercise. Signals from different layers (cutaneous tissues and muscles) during cuff occlusion were differentiated, revealing strong hemodynamic responses from muscle layers. During exercise in healthy legs, the observed ~4.7 fold increase in relative blood flow (rBF) was significantly lower than the corresponding increase in rVO2 (~7 fold). The magnitudes of rBF and rVO2 during exercise in the PAD patient were ~1/2 of the healthy controls, and the StO2 recovery time was twice that of the controls. The hybrid instrument improves upon current technologies for measuring muscle responses by simultaneously measuring rBF and StO2. The instrument thus provides a method for evaluation of microcirculation and muscle metabolism in patients with vascular diseases.
In this work, we analyze the image reconstruction problem within the first order Rytov approximation and optimize the image reconstruction by looking at the singular value spectrum of the "weight matrix". We show that the optimal data is from the tail of the temporal intensity autocorrelation curve by investigating the condition number. Furthermore, by doing a standard L-curve analysis, we find the optimal regularization constant (Tikhonov regularization). Images from simulated data are shown to illustrate the advantage of the optimization process.
A study using pregnant sheep was designed to simulate fetal hypoxia in order to investigate the ability of near-infrared spectroscopy (NIRS) to detect and quantify fetal hypoxia in utero. The near-infrared spectroscopic probe consisted of two detectors and six source positions. It was placed on the maternal ewe abdomen above the fetal head. The light sources were modulated at 70 MHz and frequency-encoded so that simultaneous measurements at 675, 786, 830 nm for each source position were possible. After the baseline measurements, fetal hypoxia was induced by blocking the aorta of pregnant ewe and thus compromising the blood supply to the uterus. Blood gas samples were concurrently drawn from the fetal brachial artery and jugular veins. Analysis of the diffuse optical data used a two-layer model to separate the maternal layer from the fetal head. The analysis also employed a priori spectral information about tissue chromophores. This approach provided good quantification of blood oxygenation changes, which correlated well with the blood gas analyses. By contrast the homogeneous model underestimated oxygenation changes during hypoxia.
A hybrid instrument combining near infrared and diffuse correlation
spectroscopies was used to measure muscle oxygenation and blood flow
dynamics during cuff occlusion and ischemia. Measurements were done on
six healthy subjects on their arm and leg flexor muscles. Hemodynamic
response was characterized for blood oxygen saturation, total
hemoglobin concenration and relative blood flow speed. The
characterization allowed us to define the normal response range as
well as showing the feasibility of using a hybrid instrument for
dynamic measurements.
Measurement of concentration, oxygenation, and flow characteristics of blood cells can reveal information about tissue metabolism and functional heterogeneity. An improved multifunctional hybrid system has been built on the basis of our previous hybrid instrument that combines two near-infrared diffuse optical techniques to simultaneously monitor the changes of blood flow, total hemoglobin concentration (THC) and blood oxygen saturation (StO2). Diffuse correlation spectroscopy (DCS) monitors blood flow (BF) by measuring the optical phase shifts caused by moving blood cells, while diffuse photon density wave spectroscopy (DPDW) measures tissue absorption and scattering. Higher spatial resolution, higher data acquisition rate and higher dynamic range of the improved system allow us to monitor rapid hemodynamic changes in rat brain and human muscles. We have designed two probes with different source-detector pairs and different separations for the two types of experiments. A unique non-contact probe mounted on the back of a camera, which allows continuous measurements without altering the blood flow, was employed to in vivo monitor the metabolic responses in rat brain during KCl induced cortical spreading depression (CSD). A contact probe was used to measure changes of blood flow and oxygenation in human muscle during and after cuff occlusion or exercise, where the non-contact probe is not appropriate for monitoring the moving target. The experimental results indicate that our multifunctional hybrid system is capable of in vivo and non-invasive monitoring of the hemodynamic changes in different tissues (smaller tissues in rat brain, larger tissues in human muscle) under different conditions (static versus moving). The time series images of flow during CSD obtained by our technique revealed spatial and temporal hemodynamic changes in rat brain. Two to three fold longer recovery times of flow and oxygenation after cuff occlusion or exercise from calf flexors in a patient with peripheral vascular disease (PVD) were found.
Changes in blood flow and oxygenation during and after PDT provide information about tumor vessel and cellular damage. The characterization of these changes may improve our understanding of PDT mechanisms and help predict treatment efficacy. We have designed a hybrid system that can non-invasively measure in vivo hemodynamic changes and provide independent information about tumor oxygenation and blood flow. Diffuse correlation spectroscopy (DCS) monitors blood flow by measuring the optical phase shifts caused by moving blood cells, while diffuse photon density wave (DPDW) spectroscopy measures tissue absorption and scattering. When mounted on a camera, our unique probe allows non-contact measurements that avoid compressing the tumor and altering blood flow. An optical filter mounted in front of the camera lens cut off light below 650nm, which allowed monitoring of blood flow during PDT. The utility of the hybrid system was demonstrated by monitoring the hemodynamic changes during and after PDT in mice bearing the experimental radiation-induced fibrosarcoma (RIF). For the first time, we non-invasively and continually monitored the in vivo flow changes during PDT. Relative oxygen consumption was calculated using flow values measured by DCS and oxygenation measured by a broadband absorption spectrometer. During PDT an initial rapid increase in blood flow was found, followed by a decrease and slow recovery. After PDT, substantial and continued reductions in blood saturation, blood flow and oxygen consumption were found after 3 hours, suggesting that permanent damage to tumor cells and blood vessels had occurred. The comparison of flow values after PDT as measured by DCS and by Power Doppler ultrasound (CWFA) demonstrated that both techniques non-invasively detected similar global changes in tumor blood flow or perfusion after PDT.
Measurement of concentration, oxygenation, and flow characteristics of blood cells can reveal information about tissue metabolism and functional heterogeneity. An instrument has been built that combines two near-infrared diffuse optical techniques to simultaneously monitor blood flow, blood volume and blood oxygen saturation. Diffuse correlation spectroscopy (DCS) monitors blood flow by measuring the optical phase shifts caused by moving blood cells, while diffuse photon density wave (DPDW) spectroscopy measured tissue absorption and scattering. The modularized design of the instrument provides the instrument great flexibility for trading off the temporal, spectral and spatial resolution by selecting the number of source-detector pairs and wavelengths. The frame acquisition rate of the current instrument is 0.2 Hz with 3? (wavelengths) × 15s (source positions) × 4d (detectors) for DPDW measurement in the frequency domain, and 1? × 3s × 9d for DCS. Higher frame acquisition rate could be achieved by reducing the spatial resolution, for example, 2 Hz with 3? × 1s × 4d for DPDW and 1? × 1s × 9d for DCS. The unique non-contact probe mounted on the back of a camera allows non-contact measurement that avoids potentially altering blood flow. We used this instrument to monitor in vivo the hemodynamic responses in rat brain during KCl induced cortical spreading depression (CSD).
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